Professional Documents
Culture Documents
Who Guidline Adult PDF
Who Guidline Adult PDF
ANTIRETROVIRAL THERAPY
FOR HIV INFECTION IN ADULTS
AND ADOLESCENTS:
Recommendations
for a public health approach
2006 revision
IMPORTANT: ADDENDUM TO 2006 WHO GUIDELINES
ON ANTIRETROVIRAL THERAPY FOR HIV INFECTION
IN ADULTS AND ADOLESCENTS
NEW DOSAGE RECOMMENDATIONS FOR STAVUDINE (d4T)
After the publication of WHO’s 2006 guidelines for HIV therapy in adults and
adolescents, the WHO Guidelines Development Group (GDG) reviewed evidence for
the use of stavudine (d4T) at reduced doses. Previously, the preferred d4T dosing was
weight-based. Dosing for patients >60 kg was recommended at 40 mg twice daily;
dosing for patients <60 kg was recommended at 30 mg twice daily.
A systematic review of nine randomized trials and six observational cohort studies
strongly suggests that stavudine-containing regimens maintain clinical and virologic
efficacy when stavudine is dosed at 30 mg twice daily, and that this reduced dose is
associated with lower rates of toxicity, especially peripheral neuropathy, compared to
the 40 mg twice daily dose. Complementary studies have also demonstrated a
significant reduction of mitochondrial DNA depletion in patients on the 30 mg twice
daily dose. However, there are limited data available about reducing the incidence of
lactic acidosis with this strategy.
Based on available evidence, the GDG has concluded that the 30 mg formulation
of stavudine, dosed twice daily, should be used for all adult and adolescent
patients, irrespective of body weight. This recommendation, which was previously
considered an option, is now established as the preferred approach when d4T is used as
part of an ARV therapeutic regimen.
Programmatic implications:
1) All new patients with weight over 60 kg being prescribed a stavudine-containing
regimen should be started on d4T 30 mg only. No patients already receiving d4T 30mg
should be stepped up to d4T 40 mg.
4) Any new procurement orders of stavudine in either single or fixed dose combinations
should only include d4T 30 mg.
References:
Antiretroviral therapy for HIV infection in adults and adolescents : recommendations for a public health approach. –
2006 rev.
«The work was coordinated by Charles Gilks and Marco Vitória of WHO/HTM/HIV, Geneva, Switzerland»--
Acknowledgements.
1.Anti-retroviral agents - therapeutic use. 2.Anti-retroviral agents - pharmacology. 3.HIV infections – drug therapy.
4.Adult. 5.Adolescent. 6.Guidelines. 7.Developing countries. I.Gilks, Charles. II.Vitória, Marco. III.World Health
Organization.
The designations employed and the presentation of the material in this publication do not imply the expression of
any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country,
territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on
maps represent approximate border lines for which there may not yet be full agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or
recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.
Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
All reasonable precautions have been taken by the World Health Organization to verify the information contained in
this publication. However, the published material is being distributed without warranty of any kind, either expressed
or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the
World Health Organization be liable for damages arising from its use.
Printed in
ANTIRETROVIRAL THERAPY
FOR HIV INFECTION IN ADULTS
AND ADOLESCENTS
Recommendations
for a public health approach
2006 revision
Acknowledgements
The preparation of this document would not have been possible without the participation of experts in the
consultations that led to the formulation of the treatment guidelines.
The World Health Organization wishes to express its special gratitude to the Guidelines Development Group, which
developed the document. The Group was chaired by Professor Scott Hammer of Columbia University (New York
City, USA). The other members of the Group were: Ayçe Riley (MASA National ARV Programme, Botswana),
Alexandra Calmy (Médecins Sans Frontières and St Vincent’s Hospital, Australia), Anthony Harries (National TB
Programme, Malawi), Chris Duncombe (HIV-NAT, Thailand), Diane Havlir (University of California at San Francisco,
USA), Ellie Katabira (Makerere University, Uganda), Fabio Scano (WHO/HTM/STB, Switzerland), Jean-Ellie Malkin
(ESTHER, France), Joep Lange (International Antiviral Therapy Evaluation Centre, Netherlands), Joia Mukerjee
(Partners in Health, USA), Judith Currier (University of California at Los Angeles, USA), Lynne Mofenson (National
Institutes of Health, NICHD, USA), Mark Harrington (Treatment Action Group, USA), Mauro Schechter (Universidade
Federal do Rio de Janeiro, Brazil), N. Kumarasamy (YRG Centre for AIDS Research and Education, India), Papa Salif
Sow (University of Dakar, Senegal), Paula Munderi (Uganda Virus Research Institute, Uganda), Sylvia Ojoo (National
AIDS and STI Control Programme, Kenya), Pedro Cahn (Fundación Huesped, Argentina), Praphan Pranuphak (Thai
Red Cross AIDS Centre, Thailand), Sergie Eholie (Treichville Hopital, Côte d´Ivoire), Wafaa El Sadr (Columbia
University, USA),William Rodriguez (Harvard Medical School and the Clinton Foundation HIV/AIDS Initiative, USA).
WHO also wishes to acknowledge comments and contributions by Annette Verster (WHO/HTM/HIV, Switzerland),
Diane Bennett (WHO/HTM/HIV, Switzerland), Donald Sutherland (WHO/HTM/HIV, Switzerland), Gerald Friedland
(Yale School of Medicine, USA), Igor Olyinik (University of Berlin, Germany), Jeroen van Gorkom (KNCV TBC,
Netherlands), Monica Alonso (WHO/AMRO,USA), Silvia Bertagnolio (WHO/HTM/HIV, Switzerland), Siobhan Crowley
(WHO/HTM/HIV, Switzerland), Paula Fujiwara (IUATLD, France), Ramzi Asfour (WHO/HTM/HIV, Switzerland) and
Ying Ru-Lo (WHO/SEARO, India).
This document was developed through an expert consultation process taking into consideration the current
scientific evidence, HIV/AIDS programme experiences and the state of the art in the treatment of HIV infection. The
primary focus was on the context of resource-limited settings.
The work was coordinated by Charles Gilks and Marco Vitória of WHO/HTM/HIV, Geneva, Switzerland.
12. Considerations for patients with tuberculosis....................................................................... 51
12.1. When to start first-line ART in patients with active tuberculosis................................. 51
12.2. What to start: recommended ART for patients with active TB.................................... 52
12.3. Women of childbearing potential or pregnant women with TB who require ART............ 53
12.4. Immune reconstitution inflammatory syndrome in patients
diagnosed with TB who start ART.............................................................................. 54
12.5. Tuberculosis in patients already receiving ART.............................................................. 54
12.6. Constructing a second-line treatment regimen for patients with an episode
of TB which indicates firt-line ART failure................................................................... 55
13. Considerations in hepatitis B or hepatitis C coinfection....................................................... 57
13.1. HBV infection.............................................................................................................. 57
13.2 HCV infection............................................................................................................. 59
14. Considerations for injecting drug users................................................................................ 61
15. Clinical and laboratory monitoring........................................................................................ 65
15.1. Baseline clinical and laboratory assessment............................................................... 66
15.2. Monitoring of patients who are not yet eligible for ART................................................ 66
15.3. Patients on ART: recommendations for clinical monitoring......................................... 67
15.4. Patients on ART: recommendations for laboratory monitoring.................................... 67
16. Adherence to antiretroviral therapy....................................................................................... 70
17. Heavily treatment-experienced patients and when to stop ART............................................ 72
18. Prevention and evaluation of drug resistance....................................................................... 73
19. Future directions to improve access to treatment in resource-limited settings.................... 77
References................................................................................................................................113
ANTIRETROVIR AL THER APY FOR HIV INFECTION
IN ADULTS AND ADOLESCENTS
1. Introduction
By the end of 2005 the World Health Organization estimated that there were just over 1.3 million
people receiving antiretroviral therapy (ART) in low-income and middle-income countries,
representing 20% of the 6.5 million estimated to need it. Since the need to close the treatment
gap was declared a global public health emergency, and the launch of the “3 by 5” initiative by
WHO and UNAIDS in December 2003, the number of people receiving ART has more than
tripled. Over the last year the number of people receiving ART globally has increased by about
300 000 every six months. Scale-up in Africa, the continent hardest hit by the HIV epidemic, has
been most dramatic, rising from 100 000 at the end of 2003 to 810 000 by the end of 2005. ART
treatment programmes in resource-poor settings have efficacy rates similar to those reported for
developed countries.1
The landscape has also changed dramatically. ART is now considered an integral part of the
comprehensive response to HIV prevention, care and support. Globally, the commitment has
been made by the G8 group of nations to universal access to ART for all who need it and this was
confirmed by the United Nations General Assembly (resolution A/60/l.43). It is hoped to achieve
this by the end of 2010.
Much of this progress has been made since the revision of Scaling up of antiretroviral therapy in
resource-limited settings: treatment guidelines for a public health approach, completed by the
end of 2003 and published by WHO early in 2004. In that document, treatment options were
consolidated into two sequential potent regimens termed first-line and second-line ART, and
approaches to simplified clinical and immunological monitoring were outlined. A recent
evaluation has noted that almost all high-burden countries have adopted or adapted the WHO
treatment guidelines to frame national recommendations. 2 Consequently, almost all the 1.3
million people currently on ART are receiving WHO-recommended first-line regimens delivered
in accordance with a public health approach. With a simple first-line adult formulary of ARVs the
production of fixed-dose first-line combinations has been encouraged, and products are
currently available from at least 23 producers. ARV prices for first-line regimens fell by between
35% and 53% from 2003 to 2005, particularly in low-income countries.
However, since 2003, considerable new evidence and programmatic experience have been
gained, necessitating a further revision of the adult guidelines. This has been done in tandem
with the revision of Antiretroviral drugs for treating pregnant women and preventing HIV infection
in infants: recommendations for a public health approach. Meanwhile, the section on paediatric
therapy has been revised and is now separately produced as Antiretroviral therapy of HIV infection
in infants and children in resource-limited settings: towards universal access; recommendations
for a public health approach.
The public health approach to the delivery of comprehensive HIV care remains the basis for all
these ARV guidelines. The public health delivery of ART focuses on maximizing survival at the
population level through standardized sequencing of the available ARVs, delivered to individuals
by means of simplified approaches and supported by clinical and basic laboratory monitoring.
It encompasses the guiding principles of chronic disease management with a strong focus on
ART adherence and integrated, decentralized health care delivery linked to reduction of HIV
transmission. Consideration is also given to the operational and programmatic requirements
necessary to achieve sustainable access to effective ART in resource-limited settings where
individualized patient management by physicians specialized in HIV medicine is not feasible.
The basic concepts of the 2003 revision of the guidelines have been retained: a standardized
formulary for first-line and second-line ART, with the use of two NRTIs and an NNRTI as the
standard first-line approach; maintenance of the PI class as the mainstay of second-line
regimens; and simplified patient management and standardized laboratory monitoring to
indicate when to start, when to substitute for toxicity, and when to switch for failure or stop
therapy (the “four Ss” of simplified clinical decision-making). WHO recognizes that, because
access to basic laboratory services continues to be limited, many treatment decisions have to
be based on clinical status alone. WHO continues to advocate wider access to monitoring tools,
particularly CD4 testing, to guide the initiation and monitoring of ART. Clinical and immunological
monitoring are supported by the recently finalized Revised WHO clinical staging and immunological
classification of HIV, and case definition of HIV for surveillance of HIV disease in adults and
adolescents, which includes presumptive and definitive criteria for classifying clinical events
related to HIV and AIDS. Previously, staging was hierarchical and irreversible. With immune
reconstitution and improvement of clinical status a new concept of staging on therapy (T-staging)
to indicate when switching should occur is being developed.
Because the previous editions of these guidelines were used extensively as a reference source
for many countries developing their own national guidelines, additional material has been
included in the 2006 revision to facilitate the key role of the document as a reference tool. There
are more detailed considerations on the use of ART in women, patients with TB/HIV coinfection
and injecting drug users (IDUs), and new sections on HIV / viral hepatitis coinfection, on the
failure of second-line therapy, and on future directions for improving access to care and
treatment.
The ARVs recommended in the standard two NRTIs/NNRTI first-line approach have been
reviewed and choices for first-line drugs have been broadened. Consideration is given to the
long-term toxicities of stavudine, widely used in national programmes as the preferred NRTI to
accompany lamivudine in first-line treatment for reasons of cost and availability. As a consequence
of these long-term toxicities, e.g. lipoatrophy, stavudine is no longer included as a preferred
drug for initial therapy in United States and European guidelines, 3 4 and WHO now recommends
zidovudine as one of the preferred NRTI options to be considered by countries. Three new
antiretrovirals (tenofovir, abacavir and emtricitabine) have been added as first-line ART options:
tenofovir and abacavir were previously recommended for second-line ART; emtricitabine is
regarded as an equivalent product to lamivudine. Tenofovir has been included because of its
excellent safety profile and ease of use (once daily). Abacavir has been added as a first-line
alternative in order to harmonize adult regimens and paediatric guidelines so as to facilitate a
comprehensive family approach. WHO recognizes that price considerations for these drugs will
remain central to the choices made in national programmes.
With these changes, a triple NRTI therapy regimen can be constructed to complement the
standard two NRTIs/NNRTI first-line approach. The use of triple NRTI therapy may be considered
as an alternative simplification approach in certain situations, such as cotreatment of tuberculosis
Second-line therapy remains based on the PI class, ideally supported by an NRTI backbone
using two new (previously unused) agents to minimize cross-resistance; ritonavir-boosted PIs
are recommended in order to enhance potency. PIs are reserved for second-line therapy. The
use of PIs in a first-line regimen essentially rules out second-line options in the setting of limited
formularies: no potent or durable options have been identified for recommendations in these
guidelines following initial PI use and failure because of the limited formularies present in the
public sector in resource-limited countries. The choice of new NRTIs for use following the failure
of an initial two NRTIs/NNRTI-based regimen remains a challenge. The efficacy of NRTIs in a
second-line regimen can be expected to be compromised by the inevitable accumulation of
NRTI mutations when switching is based on clinical or immunological failure. Viral load testing
may have a role in identifying failure and indicating when to switch in some patients, and WHO
advocates wider access to virological testing in tertiary centres and new, simpler virological
assays. WHO also strongly promotes the use of virological testing for the early definitive diagnosis
of HIV infection in HIV-exposed infants, facilitated by the use of dried blood spots and centralized
screening. However, it is not yet clear what viral load threshold best indicates failure when ART
is only available in first-line or second-line regimens and there is only one switch. Given the
continued cost and complexity of the current technology, viral load monitoring is still not suitable
for wide use in the public health management of ART. However, it is likely that the situation will
change when studies identify threshold viral load level(s) that define first-line failure, and when
simpler technology, ideally at the point of care, can be developed and made available.
2. Objectives of the document
This publication is intended to serve as a reference tool for countries with limited resources as
they develop or revise national guidelines for the use of ART in adults and postpubertal
adolescents (see Annex 9 for pubertal Tanner staging; prepubertal adolescents should follow
the WHO paediatric guidelines). The material presented takes updated evidence into account,
including new ART treatment options, and draws on the experience of established ART scale-up
programmes. The simplified approach, with evidence-based standards, continues to be the
basis of WHO recommendations for the initiation and monitoring of ART. The guidelines are
primarily intended for use by national and regional HIV programme managers, managers of
nongovernmental organizations delivering HIV care services, and other policy-makers who are
involved in the scaling up of comprehensive HIV care and ART in resource-limited countries. The
comprehensive, up-to-date technical and clinical information on the use of ART, however, also
makes these guidelines useful for clinicians in resource-limited settings. The recommendations
contained in these guidelines are made on the basis of different levels of evidence from
randomized clinical trials, high-quality scientific studies, observational cohort data and, where
insufficient evidence is available, expert opinion. The strengths of the recommendations in Table
1 are intended to indicate the degrees to which the recommendations should be considered by
regional and country programmes. Cost-effectiveness is not explicitly considered as part of the
recommendations, although the realities of human resources, health system infrastructures and
socioeconomic issues should be taken into account when the recommendations are being
adapted to regional and country programmes.
Adapted from:
1. The British HIV Association (BHIVA) treatment guidelines for 2005, http://www.bhiva.org/guidelines/2005/BHIVA-guidelines
2. Developing an evidence-based guide to community preventive services − methods. The Task Force on
Community Preventive Services. Am J Prev Med 2000;18(1S):35-43.
3. WHO Evidence Network, http://www.euro.who.int/HEN/Syntheses/hepatitisC/20050408-5
4. EBM-Guidelines, Evidence-based medicine, http://www.ebm-guidelines.com
In June 2005, WHO convened a meeting of the Guidelines Development Group (GDG) to review
existing ART recommendations for resource-limited settings. GDG was asked to review the 2003
guidelines in the light of new data and the considerable experience of scaling up ART programmes
that had been gained in many countries. GDG recognized the continued need for simple
evidence-based guidelines, for these to be revised, and for the revised recommendations to be
harmonized with the ART guidelines for infants, children and prepubertal adolescents and with
those for the use of ARVs in the prevention of mother-to-child-transmission (PMTCT).
The standardization and simplification of treatment and monitoring continues to be the prime
consideration underpinning WHO recommendations for the use of ART, in order to widen access
to effective therapy in resource-limited settings where individualized patient management by
physicians specialized in HIV medicine is not feasible. Standardized clinical and, where available,
immunological (CD4) evaluation to guide the initiation of ART, the use of appropriate formulations,
including fixed- dose combinations (FDCs) of ARVs,12 simple laboratory tools and a symptom-
directed approach to monitoring adverse events, are keys to the simplified approach.
GDG reviewed the WHO 2003 ART guidelines and considered new evidence and treatment
options with respect to:
The review suggested that the following areas should be revised and better elaborated in the
2005−2006 guidelines:
• second-line options;
• special considerations on ART with major coinfections (TB, viral hepatitis), for injecting drug
users and in pregnancy;
• salvage strategies.
GDG recognized that while the guidelines were intended primarily to provide a technical basis
for the scale-up of ART programmes at the national level, the recommendations, supported by
evidence and experience, were a powerful tool in advocating greater access to ART and could
create incentives to increase the production and reduce the cost of ARV drugs and laboratory
diagnostics (including CD4 and viral load testing). It was also necessary for the guidelines to
highlight the importance of preventing HIV secondary transmission and to emphasize that
expanding access to ART offered opportunities to enhance prevention efforts.
11
In addition to the technical recommendations on the use of ART, GDG considered that the
following key recommendations should be included in the revised guidelines.
• Wider availability of appropriate and affordable CD4 testing and plasma viral load testing
should be advocated in order to guide decision-making on when to switch ART regimens in
resource-limited settings.
• Free ART at the point of delivery or greatly reduced prices of ART to HIV-infected people
should continue to be advocated
GDG also recognized that the field of HIV therapy was rapidly evolving and that new evidence
and major advances were being regularly reported. Further revisions and updating of the
guidelines were therefore inevitable. In the interim a subgroup would continue to review new data
and evidence and would post relevant updates and recommendations on the WHO web site.
In resource-limited settings the decision to initiate ART in adults and adolescents relies on clinical
and immunological assessment. In order to facilitate the rapid scale-up of ART programmes with
a view to achieving universal access to this therapy, WHO emphasizes the importance of using
clinical parameters in deciding when to initiate it. However, it is recognized that the value of
clinical staging in deciding when to initiate and monitor ART is improved by additional information
on baseline and subsequent (longitudinal) CD4 cell counts. While WHO continues to advocate
wider availability of affordable point-of-care CD4 cell count testing, the lack of a CD4 count should
not delay the initiation of ART if the patient in question is clinically eligible. WHO encourages
national programmes to increase access to CD4 measurement technologies.
The process of initiating ART involves assessing patient readiness to commence therapy and an
understanding of its implications (lifelong therapy, adherence, toxicities). Access to nutritional
and psychosocial support and to family and peer support groups is important when decisions
are being made about the initiation of ART.
The WHO classification of HIV-associated clinical disease has recently been revised in order to
provide greater consistency between the adult and paediatric classification systems (Table 2).
Classification
of HIV-associated WHO clinical stage
clinical disease
Asymptomatic 1
Mild 2
Advanced 3
Severe 4
Clinical staging is intended for use where HIV infection has been confirmed by HIV antibody
testing. It should form part of the baseline assessment (first visit) on entry into a care and
treatment programme and is used to guide decisions on when to start co-trimoxazole prophylaxis
and when to start and switch ART in situations where CD4 testing is not available. Annexes 1 and
2 provide further details of the specific staging events and the criteria for recognizing them.
ART results in improvement in clinical status and brings about effective reversal of the clinical
stage in patients with symptomatic disease. However, the value of clinical staging in monitoring
the efficacy of ART, defining ART failure and determining when to switch ART is less clear. Studies
are urgently needed to address the use of clinical criteria (clinical stage on treatment) in deciding
when to switch ART in the absence of CD4 cell counts or viral load testing.
13
4.2. Immunological assessment of HIV-infected adults and adolescents
The optimum time to commence ART is before patients become unwell or present with their first
opportunistic infection. Immunological monitoring (CD4 testing) is the ideal way to approach this
situation. A baseline CD4 cell count not only guides the decision on when to initiate ART but is
also essential if CD4 counts are to be used to monitor ART. Table 3 summarizes the immunological
criteria for the initiation of ART.
Table 3. CD4 criteria for the initiation of ART in adults and adolescents
CD4 (cells/mm 3) a
Treatment recommendation b
a CD4 cell count should be measured after stabilization of any intercurrent condition.
b CD4 cell count supplements clinical assessment and should therefore be used in combination with clinical
staging in decision-making.
c A drop in the CD4 cell count below 200 cells/mm 3 is associated with a significant increase in opportunistic
infections and death.
d The initiation of ART is recommended for all patients with any WHO clinical stage 4 disease and some WHO
clinical stage 3 conditions, notably pulmonary TB (see Section 12.1) and severe bacterial infections.
e The initiation of ART is recommended in all HIV-infected pregnant women with WHO clinical stage 3 disease
and CD4 <350 cells/mm 3 (see Section 11.2).
The benchmark threshold marking a substantially increased risk of clinical disease progression
is a CD4 cell count of 200 cells/mm 3. Although it is never too late to initiate ART, patients should
preferably begin the therapy before the CD4 cell count drops to or below 200 cells/mm 3 [A-III].
The optimum time to initiate ART with a CD4 cell count of 200−350 cells/mm 3 is unknown.
Patients with CD4 cell counts in this range require regular clinical and immunological
evaluation.
The treatment of patients with WHO clinical stage 4 disease should not depend on a CD4 cell
count determination: all such patients should initiate ART [A-III]. For WHO clinical stage 3
conditions, a threshold of 350 cells/mm 3 has been identified as a level below which functional
immune deficiency is present and ART should be considered. This level also conforms to what
is indicated in other consensus guideline documents. 3 4 CD4 cell counts can be helpful in
categorizing patients with stage 3 conditions in respect of their need for immediate therapy. For
example, pulmonary tuberculosis or severe bacterial infections can occur at any CD4 count level
and it is reasonable to delay ART and continue to monitor patients with CD4 cell counts above
350 cells/mm 3. However, the initiation of ART is recommended for all HIV-infected individuals
with pulmonary TB and CD4 counts below 350 cells/mm 3 (see Section 12.1) and also for patients
with severe bacterial infections who have CD4 counts below this value. It is also recommended
Absolute CD4 cell counts fluctuate within individuals and can vary with intercurrent illness. If
possible, CD4 testing should be repeated if a major management decision rests on the value.
Serial measurements remain more informative than individual values because they reflect trends
over time, including the response to therapy.
In the absence of a CD4 cell count, a total lymphocyte count (TLC) below 1200 cells/mm 3 in
patients with symptomatic HIV disease has been recommended as a guide to the initiation of
ART. While the TLC correlates relatively poorly with the CD4 cell count in asymptomatic persons,
in combination with clinical staging it has been reported as a useful marker of prognosis and
survival.
It has not been possible to translate the predictive ability of TLC into a specific TLC threshold for
determining treatment eligibility. Data suggest that a TLC below 1200 cells/mm 3 as a surrogate
for a CD4 count below 200 cells/mm 3 has high positive predictive value but poor negative
predictive value and that it cannot be used alone in asymptomatic patients to determine treatment
eligibility. For the purpose of determining when to start treatment a single TLC threshold cannot
be recommended. It remains a useful predictive marker of disease progression. The TLC is thus
only useful in deciding when to initiate ART in symptomatic patients with WHO clinical stage 2
disease. It is not useful and is not recommended for monitoring the response to ART or for
deciding whether ART is failing.
The TLC should be measured with an automated reader as manual counts are too inaccurate
(especially in the presence of lymphopenia) and are too time-consuming for routine use. Many
countries with automated machines also have CD4 (bench top) measurement technology
available.
In general, ART programmes have not adopted the TLC as a trigger for initiating ART. Because
of the uncertainties surrounding the use of the TLC and its relatively infrequent use, WHO
considers that it should be gradually eliminated from the adult ARV guidelines. Better data exist
for the relationship of the TLC and HIV disease in children, and the current paediatric guidelines
continue to employ TLC thresholds for consideration of therapy when CD4 assays are not
available. Table 4 summarizes the recommendations for initiating ART in accordance with clinical
stages and the availability of immunological markers.
15
Table 4. Recommendations for initiating ART in adults and adolescents in
accordance with clinical stages and the availability of immunological
markers
WHO
CD4 testing not
clinical CD4 testing available
available
staging
a CD4 cell count advisable to assist with determining need for immediate therapy for situations such as
pulmonary TB and severe bacterial infections, which may occur at any CD4 level.
b A total lymphocyte count of 1200/mm 3 or less can be substituted for the CD4 count when the latter is
unavailable and mild HIV disease exists. It is not useful in asymptomatic patients. Thus, in the absence of
CD4 cell counts and TLCs, patients with WHO adult clinical stage 2 should not be treated.
c The initiation of ART is recommended in all HIV-infected pregnant women with WHO clinical stage 3 disease
and CD4 counts below 350 cells/mm 3 (see Section 11.2).
d The initiation of ART is recommended for all HIV-infected patients with CD4 counts below 350 cells/mm 3 and
pulmonary TB (see Section 12.1) or severe bacterial infection.
e The precise CD4 cell level above 200/mm 3 at which ARV treatment should be started has not been established.
Plasma viral load measurement is not necessary before initiating ART. It rarely informs the clinical
decision as to when ART should begin if both CD4 testing and the assessment of clinical staging
are performed. From the public health perspective, the expanded access to viral load
determination should be considered primarily for the definitive diagnosis of HIV infection in
infants and children aged under 18 months. It is hoped that more affordable methods of
determining viral load, ideally at the point of care, will become available to improve the standard
of monitoring for patients on ART, especially in situations where ART switching is being
considered.
The public health approach to ART scale-up in resource-limited settings aims to support the
development of treatment programmes that can reach as many people as possible. Countries
are encouraged to use the public health approach to support and facilitate wider access to ART.
Among the key tenets of this approach are the standardization and simplification of ARV
regimens. In the 2003 edition of these guidelines 11 it was suggested that countries select a first-
line regimen and a limited number of second-line regimens, recognizing that individuals who
cannot tolerate or fail the first-line and second-line regimens may require input from more
experienced clinicians. The use of standardized regimens has been an essential factor in
expanding access to ART and has facilitated WHO’s efforts to assist Member States in trying to
achieve this goal. The use of such regimens remains the essential approach to ARV regimen
selection adopted in this version of the guidelines, although the recommendations for the
selection of first-line and second-line regimens have been revised. When a treatment plan is
being designed it is important to maximize the durability and efficacy of any first-line regimen by
incorporating approaches that support adherence.
When selecting appropriate ARV regimens, the following factors at the programme level should
be taken into consideration:
• suitability of the drug formulation, especially the availability of fixed-dose combinations (see
Annex 10);
• licensing approval by national drug regulatory authorities for the product and recommended
dose;
• toxicity profile;
• availability from local and international manufacturers, including procurement and supply
chain logistics;
• specific ARV requirements for HIV-2 infections that are naturally resistant to NNRTIs.
For most updated information on ARVs available for resource-limited settings, consult the last edition of Sources and
prices of selected medicines and diagnostics for people living with HIV/AIDS, published by UNICEF/UNAIDS/WHO/
MSF and available at: http://www.who.int/medicines/areas/access/med_prices_hiv_aids/en/
17
The expanded number of options in the updated first-line treatment regimen recommendations does
not necessarily place increased demands on country formularies with respect to the number of
drugs to be stocked. WHO advises that country and programme managers should review these
recommendations and answer the following questions.
• What drugs should be readily available for drug substitutions for intolerance, toxicity or
special circumstances such as pregnancy and active tuberculosis?
In responding to these questions, a limited drug formulary for first-line therapy can still be
pursued in order to keep programmes as streamlined as possible. For programmes that propose
to revise their regimens a period of increased formulary complexity may exist during the transition.
WHO offers the following suggestions for programmes wishing to start or maintain an ARV rollout
with an NNRTI-based regimen.
• Choose NVP or EFV as the primary NNRTI; both should be available for mutual substitution
for toxicity and for issues related to drug choice in pregnancy and TB.
• Choose one companion NRTI to combine with 3TC or FTC in order to construct the two
NRTIs component of the regimen, and an alternative for substitution.
GDG continues to recommend that the first-line regimen for adults and adolescents contain two
NRTIs plus one NNRTI (Fig. 1). This recommendation is based on available evidence, clinical
experience and programmatic feasibility for the wider introduction of ART in resource-limited
settings [A-I]. Regimens based on combination of two NRTIs plus one NNRTI are efficacious,
are generally less expensive than other regimens, have generic formulations,12 are often available
as FDCs and do not require a cold chain. In addition, they preserve a potent new class (protease
inhibitors) for second-line treatments. Disadvantages include different drug half-lives which
complicate ART stopping procedures, the fact that a single mutation is associated with resistance
to some drugs (3TC and the NNRTIs), and cross-resistance within the NNRTI class.
The thiacytadine analogues (3TC or FTC) are pivotal to first-line regimens. 3TC or FTC should be
used with a companion nucleoside or nucleotide analogue, the choices here being AZT, TDF,
ABC or d4T.
The preferred NRTI backbone is composed of AZT or TDF combined with either 3TC or FTC [A-
I]. Didanosine (ddI) is an adenosine analogue NRTI recommended to be reserved for second-
line regimens (see Section 10.2). Finally an NNRTI, either EFV or NVP, should be added [A-I].
A triple NRTI regimen should be considered as an alternative for first-line ART in situations where
NNRTI options provide additional complications and to preserve the PI class for second- line
treatment [C-I] (e.g. in women with CD4 counts of 250−350 cells/mm 3; coinfection with viral
hepatitis or tuberculosis; severe adverse reactions to NVP or EFV, infection with HIV-2).
Recommended triple NRTI combinations are zidovudine + lamivudine + abacavir [A-I] and
zidovudine + lamivudine + tenofovir [A-II] (See Fig. 1).
AZT or d4T
2
EFV
3TC or FTC
TDF or ABC
2
NVP
Triple NRTI approach 3
1 Preferential two NRTIs/NNRTI approach is based upon a combination of three drugs: two NRTIs combined with
either NVP or EFV as the NNRTI.
2 Preferred NRTI to be combined with 3TC or FTC in standard first-line regimens.
3 Triple NRTI approach (i.e. three NRTI drugs selected only from the options shown within the dotted circle) can
be considered as an alternative for first-line regimens in situations where NNRTI options provide additional
complications (e.g. women who have CD4 counts between 250 and 350 cells/mm 3, viral hepatitis coinfection,
TB coinfection, severe reactions to NVP or EFV, and HIV-2 infection) as discussed above.
Despite the expanded recommendations for TDF and ABC use in first-line regimens, many
countries may prefer to continue maintaining these two NRTI options in second-line regimens.
Regardless of whether they are used as first-line or second-line therapy, it is very important to
include these two drugs in all national ARV formularies.
19
5.3. Notes on ARV combinations to be avoided or used with caution
Monotherapy or dual therapy should not be used to treat chronic HIV infection; they may only be
used in the setting of PMTCT and post-exposure prophylaxis. Certain dual NRTI backbone
combinations should not be used within three-drug therapy. These are d4T + AZT (proven
antagonism), d4T + ddI (overlapping toxicities) and 3TC + FTC (interchangeable, but should not
be used together). The combinations of TDF + 3TC + ABC and TDF + 3TC + ddI select for the
K65R mutation and are associated with high incidences of early virological failure. The
combinations of TDF + ddI + any NNRTI are also associated with high rates of early virological
failure. However, the use of ddI should be reserved for second-line treatment, in which situation
it is possible to consider TDF + ddI with boosted PIs, provided that caution and close monitoring
are practised, until more data become available [B-IV]. The ddI dose should be adjusted when
used concomitantly with TDF in order to reduce the toxicity risk (see footnote in Annex 3).
Lamivudine (3TC) has been and remains pivotal to all first-line ARV regimens in resource- limited
settings. It is a core component of the dual NRTI backbone in all ARV combinations. It has
proved safe, has a favourable toxicity profile, is nonteratogenic, is effective against hepatitis B
infection, is relatively cheap to produce and is widely available, including in fixed- dose
combinations (FDCs).
Emtricitabine (FTC) is a new NRTI that has recently been included in WHO’s recommended first-
line regimens. FTC is an equivalent alternative to 3TC as it is structurally related to 3TC, shares
the same efficacy against HIV and hepatitis B virus and has the same resistance profile.13 It is
available as an FDC with TDF and, recently, a formulation with TDF, and EFV as a single, “three-
in-one” pill was approved for clinical use. FTC is not yet on the WHO list of essential
medications.
Zidovudine (AZT) is included as a preferred first-line NRTI. It is generally well tolerated and
widely available in some FDCs (see Annex 10). Initial drug-related side-effects are headache
and nausea, and it can also cause severe anaemia and neutropenia. Haemoglobin monitoring
is recommended before and during treatment with AZT. This is particularly important in areas
with a high prevalence of malaria, where anaemia is common. AZT is associated with metabolic
complications, such as lactic acidosis and lipoatrophy, but to a lesser extent than d4T.
Tenofovir (TDF) is now included as a preferred first-line NRTI, because of its efficacy, ease of use
and safety profile. This is a change from the 2003 guidelines, which recommended reserving the
use of TDF as part of second-line regimens. TDF has a long intracellular half-life and can be
used as part of once-daily regimens. It is generally well tolerated and studies suggest that it is
not more frequently associated with renal dysfunction than other antiretroviral drugs.14 15 Despite
some reports of renal insufficiency in patients receiving TDF, the occurrence of renal dysfunction
in this context is usually attributable to other causes. The dose of TDF should be reduced in
patients with underlying renal insufficiency. Because of limited data and concerns about potential
Abacavir (ABC) has been included in these revised guidelines as an alternative NRTI in first-line
therapy. This is a change from the 2003 guidelines, in which reserving the use of ABC as part of
second-line regimens was recommended. NRTI combinations containing ABC provide an
effective NRTI backbone for use with NNRTIs or as part of a triple nucleoside regimen. Of all the
NRTI drugs, ABC has the least effect on mitochondrial DNA depletion (associated with
lipoatrophy, peripheral neuropathy and lactic acidosis) and is one of the possible substitutes for
d4T or AZT in patients who develop lactic acidosis while receiving a regimen containing d4T or
AZT. ABC can also be substituted for AZT in the event of intolerance. However, ABC is associated
with a severe hypersensitivity reaction in approximately 2−5% of patients who receive the drug.
The accurate determination of rates of ABC hypersensitivity in resource-constrained settings is
an important clinical research objective.
Two of the reasons for including ABC in first-line recommendations for adults in these guidelines
are: 1) clinical trial results in naive patients have demonstrated efficacy; 2) it is one of the few
drugs available in a paediatric formulation. Thus, programme managers who wish to deliver
family-based care to HIV-infected parents and children may find ABC/3TC an attractive dual
NRTI component option to pursue if it can be made affordable. Despite being registered in many
developing countries, its availability is currently limited by high cost.
Stavudine (d4T) is recognized as a life-saving drug that has played a crucial role in ART rollout,
especially because of its availability in fixed-dose combinations (see Annex 10), the low cost of
these FDCs and the clinical efficacy of the regimens recommended. d4T has also been preferred
over AZT because of the requirement for limited or no laboratory monitoring. However, d4T has
been consistently the NRTI most associated with lactic acidosis, lipoatrophy and peripheral
neuropathy.16 The latter toxicities are cumulative and often irreversible, and have the potential to
affect adherence in the long term. The stigmatization associated with lipoatrophy can result in
withdrawal from or refusal to enrol in ART programmes. Programmes that are dependent on d4T-
based regimens may need to follow through with their current strategies so that needed treatment
for individuals is not delayed. Because of the current wide availability in FDCs and considerably
lower prices, d4T-containg regimens may still remain the most accessible option for people in
urgent need of treatment in resource-limited settings in the short to medium term. At the same
time, WHO notes that it is important to begin planning to move away from d4T-containing regimens
so as to avoid or minimize the predictable toxicities associated with this drug. This recommendation
is in agreement with other treatment guidelines, e.g. those published by the United States
Department of Health and Human Services (DHHS) and the British HIV Association (BHIVA).
In the transition to safer first-line ARV choices, enhanced and closer monitoring for short-term
and long-term d4T toxicities is recommended. This includes the training of health care workers
and adequately informing patients of the signs and symptoms of lactic acidosis, lipoatrophy and
peripheral neuropathy. Early recognition of d4T side-effects and switching to an alternative NRTI
21
(such as AZT, TDF or ABC) may reduce the severity of these drug toxicities. d4T may be used as
a substitute for AZT if intolerance occurs and TDF and ABC are unavailable.
The role of dose reduction in mitigating d4T toxicity is uncertain. Because of the nature of the
mitochondrial damage (cumulative toxicity), dose reduction may not prevent the occurrence of
side-effects, and can at best delay the onset of symptoms. Some data suggest that dose
reduction may be associated with a lower incidence of adverse events without compromising
virological control.17 However, dose reduction to 30 mg twice daily irrespective of weight can be
a strategy to consider in the absence of alternatives (see Section 7.2).
NNRTIs are potent and the key ARV class to be combined with a dual NRTI backbone in first-line
therapy and facilitate the construction of relatively simple initial regimens. The NNRTIs efavirenz
(EFV) and nevirapine (NVP) both have demonstrated clinical efficacy when administered in
appropriate combination regimens. However, differences in toxicity profile, the potential for
interaction with other treatments, and cost have to be considered when an NNRTI is being
chosen.18 19 It is also necessary to take into account the inactivity of NNRTIs against HIV-2 infection
and the fact that a single mutation can confer NNRTI class-wide drug resistance in HIV-1.
Nevirapine (NVP) is widely available (including in several FDCs) and is less costly than EFV.
Moreover, significant experience has been gained with this drug at country level in resource-limited
settings. However, a higher incidence of rash is associated with it than with EFV.18 NVP-related rash
may be severe and life-threatening, and Stevens-Johnson syndrome may occur. NVP is also
associated with a rare but potentially life-threatening risk of hepatotoxicity. This makes the drug
less suitable for treating patients who use other hepatotoxic medications. The initiation of NVP at
the same time as other new drugs that can also cause rash (e.g. co-trimoxazole) should be avoided
where possible. In the case of severe hepatic or skin reactions, NVP should be permanently
discontinued and not restarted (see Section 8). NVP is the preferred NNRTI for women if there is
potential for pregnancy or during the first trimester of pregnancy, when EFV cannot be used
because of its teratogenic effect. However, symptomatic NVP-associated hepatic toxicity or serious
rash, while uncommon, is more frequent in women than in men, and more likely to be seen in
antiretroviral-naive women with higher CD4 cell counts (above 250 cells/mm3). Thus, NVP should
be used with caution in women with CD4 counts between 250 and 350 cells/mm 3. If it is used,
careful monitoring is needed during the first 12 weeks of therapy (see Section 11.2.3). Annex 3
provides more detailed information on dosing and preparations of the above-listed drugs.
Efavirenz (EFV) can be used once daily and is generally well tolerated. However, it is relatively
costly and currently less widely available than NVP. It is primarily associated with toxicities
related to the central nervous system (CNS), teratogenicity and rash. Rash is generally mild, self-
resolving and usually does not require the discontinuation of therapy. The CNS symptoms
typically abate after two to four weeks in the majority of patients. EFV should be avoided in
patients with a history of severe psychiatric illness, when there is a potential for pregnancy
(unless effective contraception can be assured) and during the first trimester of pregnancy. In
The 2003 revision of these guidelines attempted to place triple NRTI-based regimens in
perspective for resource-limited settings. A single study noted inferior virological efficacy (21%
vs 10% virological failure rates for AZT + 3TC + ABC triple NRTI vs EFV-based ART regimen at
32 weeks) but comparative immunological efficacy of AZT + 3TC + ABC was reported vs AZT
+ 3TC + EFV or AZT + 3TC + ABC + EFV in AIDS Clinical Trials Group (ACTG) Study A5095. 20
These findings led to the recommendation that this triple NRTI regimen be moved to alternative
tier status for initial therapy. This was consonant with consensus recommendations in
industrialized countries at the time and had little impact on ARV rollout programmes in the
developing world because of the cost of ABC and the AZT + 3TC + ABC fixed-dose combination.
It was recommended that AZT + 3TC + ABC should remain a consideration in the setting of
intolerance or resistance to NNRTIs when PI-based regimens were unavailable, and that second-
line options should be preserved for the treatment of HIV-2 infection and of HIV/TB coinfected
individuals when the treatment of both conditions simultaneously was indicated.
Important new data have emerged from the DART Trial, which used a TDF-based triple NRTI
regimen 21. In the DART virology substudy, of 300 persons who were treated with AZT + 3TC +
TDF, 65% and 55% exhibited plasma HIV-1 RNA levels below 400 and 50 copies/ml respectively
at 48 weeks of follow-up. These results should be interpreted with caution, given the lack of a
control group and because, in other studies, EFV-containing regimens have achieved higher
virological suppression rates. However, the DART results suggest the possibility that this regimen
may have a useful role in first-line treatment.
Clearly, each triple NRTI regimen should be evaluated individually. While AZT + 3TC + ABC and
AZT + 3TC + TDF have virological response rates that remain within an acceptable standard-of-
care range, other triple NRTI regimens (e.g. 3TC + ABC + TDF and 3TC + ddI + TDF) have
unacceptably high virological failure rates and high incidences of the K65R mutation, 22 23 which
confers cross-resistance to non-AZT nucleoside analogues. These regimens should not be used.
It is recommended that PIs be reserved for second-line therapy because their use in an initial
treatment regimen essentially rules out second-line options in the setting of limited formularies
within a public health approach: no potent or durable regimens have been identified for
recommendation following initial PI failure in this situation. With this important caveat, PIs as
initial therapy with a standard dual NRTI backbone are an option for the treatment of viral types
with intrinsic resistance to NNRTIs (e.g. HIV-2), for women with CD4 counts of 250−350 cells/
mm 3, or for individuals for whom NNRTI drugs are severely toxic and triple NRTI therapy is not
available or deemed inappropriate.
23
6. What to expect in the first six months of therapy
The first six months on ART are critical. Clinical and immunological improvement should manifest
themselves but are not always apparent and drug toxicities may emerge. Some patients fail to
respond as expected or may even exhibit clinical deterioration initially. These issues combine to
present specific challenges for simplified clinical management. Complications in the first few
weeks following the initiation of ART are seen most commonly when therapy is started in patients
with severe immunodeficiency. The apparent failure of a patient with advanced HIV disease to
improve initially does not necessarily reflect a poor response to ART. It takes time for HIV viral
replication to be controlled by ART and for the patient’s immune system to strengthen. It also
takes time for reversal of the catabolism associated with HIV infection, particularly in patients
with significant HIV-associated wasting. Additionally, as a patient with advanced disease
recovers immune function, exacerbation of previously subclinical coexisting infections (e.g.
tuberculosis) may occur, resulting in an apparent worsening of disease. This is not attributable
to failure of the therapy but to its success and the resulting immune reconstitution (see Section
6.4). Such symptoms might be interpreted as an initially poor response to ART. It is important to
allow sufficient time on therapy before judging effectiveness and to consider the possibility of
the immune reconstitution inflammatory syndrome (IRIS) in patients with worsening disease in
the first few months of ART. In such cases, the switching of ART would be inappropriate.
In most patients, CD4 cell counts rise with the initiation of therapy and immune recovery. This
may continue for many years into effective therapy, although this may be blunted if the baseline
CD4 count is very low. However, even patients with CD4 counts below 10 cells/mm 3 can achieve
an effective CD4 recovery, given sufficient time after the initiation of ART. Some patients may
never have CD4 counts that exceed 200 cells/mm 3 and thus never leave the zone of severe
immunosuppression. In those who achieve a substantial peak response, a subsequent
progressive decline in CD4 counts in the absence of intercurrent illness indicates immunological
failure. The baseline CD4 count and the trend of the CD4 response assessed by regular six-
monthly CD4 counts are needed to best characterize and define immunological failure (see
Section 8). In a minority of patients with advanced disease and low CD4 counts when therapy is
initiated, the CD4 counts may not rise or may fall slightly, even with clinical improvement.
First-line drug toxicities fall into two categories: early, usually presenting in the first few weeks to
months of therapy, and later (see Section 7). Common early and potentially severe toxicities are
hypersensitivity to NNRTIs (EFV and NVP), normally occurring within the first few weeks of
therapy, and AZT-related anaemia and neutropenia, typically presenting in the first few months
of therapy. Many of the acute toxicities, if not identified early, can evolve into life-threatening and
fatal events. Some of the higher mortality seen in the first six months of ART undoubtedly relates
to drug toxicity. Currently, limited pharmacovigilance data are available for assessing the exact
impact of ART toxicity on early mortality.
While ART significantly decreases mortality, the latter is higher in the first six months than during
the subsequent time on therapy, particularly when patients start with stage 4 clinical events,
severe immunosuppression and very low CD4 counts. The ART-LINC collaboration (18 treatment
programmes in Africa, Asia and South America) recorded a 4% mortality rate in 2725 patients
under active follow-up six months after starting therapy but noted that mortality fell to 2% in the
subsequent six months of therapy. The DART trial reported that 39 of 62 deaths (63%) in a cohort
of over 1000 adults followed for two years occurred in the first six months of therapy.
In the Médecins Sans Frontières (MSF) cohort of over 6000 patients treated with a generic FDC
of d4T + 3TC + NVP, almost 70% of deaths occurred during the three first months after ART
initiation. 26 This greater risk of death is seen especially in patients with disseminated TB (and
other severe OIs) and a pre-ART CD4 cell count <50 cells/mm 3. 27 28 29
The immune reconstitution inflammatory syndrome (IRIS) is a spectrum of clinical signs and
symptoms resulting from the restored ability to mount an inflammatory response associated with
immune recovery. 30 It can present with the signs and symptoms of a previously subclinical and
unrecognized opportunistic infection, as a paradoxical worsening of treatment response several
weeks into therapy, or as an autoimmune disease such as Graves disease (hyperthyroidism) in
the context of immune recovery on ART. Typically, IRIS occurs within two to twelve weeks of the
initiation of ART, although it may present later. The incidence of IRIS is estimated to be 10%
among all patients initiating ART and up to 25% among patients initiating ART with a CD4 cell
count below 50 cells/mm 3. 31 32 However, the clinical syndromes associated with IRIS in resource-
limited settings have been relatively poorly described and it is not known whether there are any
important regional variations in the clinical spectrum.
Risk factors predicting the likelihood of IRIS include initiating ART close to the time of diagnosis of
an opportunistic infection, being antiretroviral-naive at the time of diagnosis of an opportunistic
infection, initiating ART when the CD4 count is below 50 cells/mm3, and having a more rapid initial
decrease in the HIV-1 RNA level in response to ART than in patients with higher CD4 counts. 33
IRIS has been reported in association with a large number of HIV-related infections and
inflammatory conditions. 34 35 The most frequently occurring IRIS events are associated with
25
mycobacterial disease (tuberculosis or Mycobacterium avium complex infection) and cryptococcal
disease. Together, mycobacterial and cryptococcal disease account for approximately 60% of
all cases of IRIS in developed country settings. 36
IRIS may be mild and resolve without treatment, e.g. it may involve a transient flare of hepatic
enzymes in a patient with HIV/hepatitis B coinfection, or it may be severe and life-threatening, as
in patients with cryptococcal meningitis or tuberculosis. 37 38 The development of a new or
recurrent OI soon after ART initiation does not indicate treatment failure and is not an indication
to stop or switch ART. If possible, ART should be continued and the OI or inflammatory condition
should be treated. 39 If this is impossible, ART should be temporarily interrupted, the OI or
inflammatory condition should be treated, and the same ART regimen should be restarted.
The management of IRIS includes treatment of the causative pathogen in order to decrease the
antigenic load, continuation of ART, and the use of corticosteroids. The dose and duration of
corticosteroid treatment is unclear. Prednisolone (or prednisone) at 0.5 mg/kg/day for five to ten
days is suggested in moderate to severe cases of IRIS.40
Antiretroviral agents are responsible for a broad range of toxicities, ranging from low-grade
intolerances that may be self-limiting to life-threatening side-effects. One of the many challenges
of the public health approach is to develop educational tools for patients and health care
providers which can assist with the ready identification of drug-specific side-effects so that
appropriate measures to alleviate or eliminate them can be taken. This is essential for patient
safety and if drug adherence is to be maintained and interruption of treatment avoided.
Differentiating between complications of HIV disease and ART toxicity (also known as adverse
events) is sometimes difficult. Alternative explanations for a patient’s presenting symptoms
should be considered before it is concluded that toxicity is ART-related. Considerations include
intercurrent illness (e.g. hepatitis A virus infection in patients with symptoms of hepatitis, or
malaria in patients with severe anaemia), or a reaction to medications other than ARVs, e.g.
isoniazid-induced hepatitis or peripheral neuropathy, and rash induced by co-trimoxazole.
Drug-related adverse events can occur early (the first few weeks or months of treatment) and late
(after six months or more of treatment). Adverse events can vary in severity from mild to severe and
life-threatening. ARV toxicity may be specific to the drug or to the class of drugs in use.
Substitution within the first-line regimen in the context of individual drug toxicity is recommended.
The decision to substitute a new ARV depends on the ability to attribute the toxicity to a specific
ARV drug and on the severity of the toxicity symptoms (see Table 6).
27
As a general principle, mild toxicities do not require discontinuation of therapy or drug substitution,
and symptomatic treatment may be given. Moderate or severe toxicities may require substitution
with a drug in the same ARV class but with a different toxicity profile. Severe life-threatening
toxicity requires discontinuation of all ARV drugs until the patient is stabilized and the toxicity is
resolved. NNRTIs have a longer half-life than NRTIs, leading to a concern that stopping all drugs
simultaneously may lead to exposure to drugs from the NNRTI class only and the possibility of
resistance developing to the NNRTIs. However, if the patient has a life-threatening toxicity, all
ARV drugs should be stopped simultaneously until the patient is stabilized. If the toxicity is
attributable to the NNRTI component the concern about resistance may not matter, as NNRTIs
may not be subsequently used.
Regardless of their severity, adverse events may affect adherence to therapy. A proactive
approach to managing toxicity is recommended. Discussing the potential side-effects of the
ART regimen with the patient before the initiation of therapy and during the early stages of
treatment, as well as support during minor and moderate adverse events, can increase the
likelihood of adherence to therapy (see Section 16). The patient should be familiar with signs and
symptoms of toxicities that are serious and require immediate contact with the health care team.
This is particularly important for toxicities that can be life-threatening, including NVP-associated
Stevens-Johnson syndrome, hepatitis, lactic acidosis or ABC-associated hypersensitivity
reaction.
3. Consider other disease processes (e.g. viral hepatitis in an individual on ARV drugs who
develops jaundice) because not all problems that arise during treatment are caused by
ARV drugs.
• Grade 3 (severe reactions): Substitute the offending drug without stopping ART.a
• Grade1 (mild reactions) are bothersome but do not require changes in therapy.
5. Stress the maintenance of adherence despite toxicity for mild and moderate reactions.
6. If there is a need to discontinue ART because of life-threatening toxicity, all ARV drugs
should be stopped until the patient is stabilized.
Most initial regimens used in ARV scale-up since 2003 have included AZT or d4T with 3TC and
NVP or EFV. The predominant toxicities have included the adverse events expected from the use
of these drugs in other settings, e.g. anaemia, peripheral neuropathy, lactic acidosis, and, in
cohorts with more than one year of treatment, lipoatrophy.
In a study in India between 1996 and 2004, 1443 ART-naive patients received regimens containing
d4T or AZT. The most common toxicities were rash (66%), hepatotoxicity (27%) and anaemia
(23%).41 In Abidjan, Côte d’Ivoire, 498 adults with a median baseline haemoglobin of 113 g/l
started AZT + 3TC + EFV; 118 patients had grade 3/4 neutropenia and 23 had grade 3/4
anaemia. Of these patients, 80% were taking co-trimoxazole, which can cause anaemia and
neutropenia.42 In the DART study being conducted in Uganda and Zimbabwe, 219 of 3314
participants (6.6%) developed grade 4 anaemia by week 48; in the same study, ABC
hypersensitivity reactions were reported in 2% of participants.
29
In Tororo, Uganda, 1073 patients were treated with d4T + 3TC + NVP. The probabilities of
remaining free of severe toxicity at 6, 12 and 18 months were 92%, 86% and 84% respectively,
whereas nearly 50% of the patients experienced some form of toxicity by 18 months. Toxicity
requiring a change in therapy occurred in 21% of the cohort, most commonly a switch from d4T
to AZT. In Nairobi, Kenya, 284 patients received d4T + 3TC + NVP and the reported toxicity-free
survival rate was 21% at 18 months. However, over 95% of patients remained on their original
regimen despite these events. In a report from Khayelitsha, South Africa on 1700 patients
receiving ART, one agent was substituted in approximately 10% because of toxicity. The rates
were similar for d4T (8.5%), AZT (8.7%) and NVP (8.9%).
The major ART-related metabolic abnormalities are lactic acidosis, dyslipidaemia, morphological
changes (fat accumulation and lipoatrophy), dysregulation of glucose metabolism, and reduced
bone mineral density. The cluster of metabolic abnormalities together with fat redistribution
(peripheral lipoatrophy and central fat accumulation) have been termed the HIV lipodystrophy
syndrome. Adverse metabolic effects of potent antiretroviral therapy are a major concern because
they may stigmatize the patient and because hyperlipidaemia and insulin resistance may
increase the long-term risk of cardiovascular disease.43 Rates of metabolic complications have
been relatively poorly recorded in ART programmes in resource-limited settings. Better data are
needed and improved pharmacovigilance is an important programme priority.
In settings where serum lactate is not available, calculating the anion gap (anion gap = [Na + K] – [HCO3 + Cl], normal
6−12 mmol/l), is an alternative.
Surgical options exist for both lipoatrophy (facial filling with collagen, synthetic polymers or
silicone, or autologous fat transplantation) and lipodystrophy (liposuction). These options
provide cosmetic improvement but may only give temporary benefit, especially if the patient
continues to take an ARV drug that is associated with fat redistribution.
7.2.4. Dyslipidaemia
PIs (with the exception of unboosted atazanavir 52), EFV and NRTIs can cause elevations in
triglycerides and cholesterol. d4T and AZT are associated with greater rises in triglycerides and
cholesterol than TDF in treatment-naive patients. Severe triglyceride elevations (i.e. grades 3 or
4, see Annex 7) may be associated with pancreatitis. Routine monitoring of lipid levels is not
currently feasible in many settings and is not needed to support ART.
31
8. Drug substitutions because of toxicity
The general principle is that single-drug substitution because of toxicity should involve drugs
belonging to the same ARV class. If toxicity is related to an identifiable drug in a regimen the
offending drug can be replaced with one that does not have the same side-effects (e.g. substitution
of AZT or TDF for d4T in cases of neuropathy, TDF or d4T for AZT where anaemia occurs, or NVP
for EFV for CNS toxicity or in pregnancy). Given the limited number of ARV drug options available
in resource-limited settings, drug substitutions should generally be limited to situations where
toxicity is moderate to severe (grade 3) or life-threatening (grade 4) (see Annex 7).
Table 7 lists the usual ARV substitution options in instances of toxicity involving the ARVs
recommended in first-line regimens.
Lactic acidosis
TDF or ABC d
d4T Lipoatrophy / metabolic syndrome e
Hypersensitivity reaction
NVP
Severe or life-threatening rash (Stevens- TDF or ABC (or any PI h)
Johnson syndrome) g
The substitution of EFV for NVP following a non-severe (grade 1 or 2) NVP-related rash and/or
hepatotoxicity is recommended, together with careful monitoring [B-IV].
For life-threatening or more complex clinical situations, consultation with and/or referral to district
or regional hospital centres is recommended. When a severe or life-threatening toxicity occurs it
is appropriate to temporarily discontinue the entire ARV regimen until the toxicity has resolved.
A revised regimen can then be introduced.
For some life-threatening toxicities it may not be possible to identify an optimal substitute drug
within the drug class concerned. For example, in the case of NVP-associated Stevens-Johnson
Syndrome, substitution with another NNRTI drug is not recommended because of the potential
for class-specific toxicity [B-IV], although this approach has been evaluated in a small number
of patients in Thailand without recurrent rash. This situation would require a change to either a
triple NRTI regimen (e.g. substituting a third NRTI, e.g. ABC or TDF, for NVP if AZT/3TC was the
original dual NRTI component), or substituting a protease inhibitor for NVP, thereby introducing
a drug class reserved for second-line regimens. If a PI is used, it must be noted that no potent
and durable regimens have been identified for recommendations following initial PI failure (see
Section 5.7).
33
9. Antiretroviral treatment failure
and when to switch therapy
The decision on when to switch from first-line to second-line therapy is critical. If the decision is
made too early the months or years of potential further survival benefit from any remaining first-
line effectiveness is lost; if it is made too late, the effectiveness of second-line therapy may be
compromised and the patient is put at additional and appreciable risk of death. The time of
switching is dictated by treatment failure, and this can be measured in three ways: clinically, by
disease progression and WHO staging; immunologically, using trends in CD4 counts over time,
and virologically, by measuring HIV viral loads (plasma HIV-1 RNA levels). However, the definitions
of clinical, immunological and virological failure currently used in different settings represent
different biological end-points. It is not clear which criteria are optimal, as either individual
measures or a mix of measures. There is an urgent need for agreement on defining treatment
failure and for standardization across the different ways of identifying it.
There is a limited amount of data and programme experience which can inform decisions about
the optimal time to switch therapy in the first-line/second-line approach based on any of these
monitoring strategies. Second-line regimens have not been widely available in the public sector,
and even where they are available, first-line therapy has proved highly effective with little (clinical)
failure identified at up to three years of follow-up. There are also significant constraints in using
each of the three different approaches to the definition of failure.
• The value of immunological monitoring in defining ART failure largely depends on having a
baseline CD4 count before commencing ART and on having longitudinal CD4 measurements
on ART. One-off (spot) CD4 counts on ART are difficult to interpret when making decisions
about treatment success or failure.
• Viral load measurements are not widely available and will remain restricted because of cost
and accessibility. Switching therapy with any detectable virus (as recommended in
industrialized countries where multiple individualized treatment regimens can be used) is an
extremely conservative definition of failure and is too early in the public health approach.An
appropriate threshold for switching regimens remains to be determined and is a research
priority; some evidence suggests that 5000 to 10 000 copies/ml may be an appropriate
threshold.53 54 55 56
For the purposes of these guidelines, recommendations for switching from first-line to second-line
therapy are based on the assumption that most countries only make provision for second-line
regimens in the public sector. In this circumstance, premature switching to the second-line regimen
needs to be avoided. The situation is further complicated because, for many programmes,
monitoring is based primarily on clinical criteria, and even if CD4 cell count monitoring is available
its frequency is probably limited. This clinical situation represents another argument for having
CD4 cell quantitation universally available in resource-limited settings and for moving as quickly as
Table 8. Clinical, CD4 cell count and virological definitions of treatment failure
for patients on a first-line antiretroviral regimen
CD4 cell failure d • Fall of CD4 count to pre-therapy baseline (or below); or
• 50% fall from the on-treatment peak value (if known); or
• persistent CD4 levels below 100 cells/mm3 e
a Current event must be differentiated from the immune reconstitution inflammatory syndrome.
b Certain WHO clinical stage 3 conditions (e.g. pulmonary TB, severe bacterial infections), may be an indication
of treatment failure and thus require consideration of second-line therapy.
c Some WHO clinical stage 4 conditions (lymph node TB, uncomplicated TB pleural disease, oesophageal
candidiasis, recurrent bacterial pneumonia) may not be indicators of treatment failure and thus do not require
consideration of second-line therapy.
d Without concomitant infection to cause transient CD4 cell decrease.
e Some experts consider that patients with persistent CD4 cell counts below 50/mm 3 after 12 months on ART
may be more appropriate.
f The optimal viral load value at which ART should be switched has not been defined. However, values of more
than 10 000 copies/ml have been associated with subsequent clinical progression and appreciable CD4 cell
count decline.
It should not be concluded, on the basis of clinical criteria, that an ARV regimen is failing until
there has been a reasonable trial of first-line therapy lasting at least six to twelve months,
adherence has been assessed and optimized, intercurrent opportunistic infections have been
treated and resolved, and IRIS has been excluded. Clinical events that occur before the first six
months of therapy are excluded from this definition of failure because they often represent immune
reconstitution inflammatory syndromes related to pre-existing conditions (see Section 6).
The development of a new or recurrent WHO stage 3 or 4 condition on treatment (but after the
first six months of ART) is considered functional evidence of HIV disease progression. This is
being referred to as T staging, where T refers to the staging event on treatment. The assumption
is that with immune restoration on ART, and the subsequent progressive immunodeficiency with
a failing ART regimen, the clinical events signalling immune failure will be the same as those
heralding advanced and then severe immunodeficiency without ART. Table 9 indicates how
clinical staging on ART can be used as an indicator of failure and prompts consideration of the
need to switch therapy.
35
Table 9. Clinical staging events to guide decision-making on switching
New or
Additional management
recurrent event Recommendations
options
on ART a
• Maintain scheduled follow-up visits,
Asymptomatic including CD4 monitoring (if available)
Do not switch regimen
(T1) • Continue to offer adherence support
a Refers to clinical stages while on ART for at least six months (termed T1, T2, T3, T4).
b Differentiation of opportunistic infections from immune reconstitution inflammatory syndrome is necessary.
c Treat and manage the staging event before measuring CD4 cell count.
d Certain WHO clinical stage 3 conditions (e.g. pulmonary TB, severe bacterial infections) may be indicators
of treatment failure and thus require consideration of second-line therapy; response to appropriate therapy
should be used to evaluate the need for switching of therapy.
e Some WHO clinical stage 4 conditions (lymph node TB, uncomplicated TB pleural disease, oesophageal
candidiasis, recurrent bacterial pneumonia) may not be indicators of treatment failure and thus do not require
consideration of second-line therapy; response to appropriate antimicrobial therapy should be used to
evaluate the need to switch therapy.
The CD4 cell count remains the strongest predictor of HIV-related complications, even after the
initiation of therapy.57 58 The baseline pretreatment value is informative: lower CD4 counts are
associated with smaller and slower improvements in counts. However, precise thresholds that
define treatment failure in patients starting at various CD4 levels are not yet established. As a
general rule, new and progressive severe immunodeficiency as demonstrated by declining
longitudinal CD4 cell counts should trigger a switch in therapy. Ideally, any measurement that
may indicate the need to consider switching should be repeated and the low level confirmed
before any change is implemented.
Patients starting with low CD4 counts may demonstrate slow recovery, but persistent levels
below 100 cells/mm 3 represent significant risk for HIV disease progression. Caveats to be noted
are that intercurrent infections can result in transient CD4 count decreases, and that, with
relatively infrequent monitoring (e.g. every six months), the true peak of the CD4 cell count may
be missed. As a general principle, intercurrent infections should be managed, time should be
allowed for recovery and the CD4 cell count should be measured before ART is switched. If
resources permit, a second CD4 cell count should be obtained to confirm immunological
failure.
Reasonable working definitions of immunological failure are: (1) CD4 count below 100 cells/mm 3
after six months of therapy; (2) a return to, or a fall below, the pre-therapy CD4 baseline after six
months of therapy; or (3) a 50% decline from the on-treatment peak CD4 value (if known).
The CD4 cell count can also be used to determine when not to switch therapy, e.g. in a patient
with a new clinical stage 3 event for whom switching is being considered or in a patient who is
asymptomatic and under routine framework. In general, switching should not be recommended
if the CD4 cell count is above 200 cells/mm 3.
Although viral load testing is not yet widely available, it is a sensitive and informative way to
identify treatment failure. When treatment failure is defined on the basis of clinical and/or CD4
criteria the diagnosis may be made later than when viral load is being monitored. Diagnosing
treatment failure based on clinical or CD4 criteria alone will provide a greater opportunity for the
selection of drug resistance mutations before regimen change and may compromise particularly
37
the NRTI component of the second-line regimen through increasing class-wide drug resistance.
This provides another strong argument for moving towards the wider availability of plasma viral
load testing in resource-constrained settings. In particular, simple point-of-care assays are
needed which identify, qualitatively or semiquantitatively, viral load thresholds that inform clinical
management decisions.
Viral load testing is already available in some centres and programmes. However, the viral load
threshold triggering a switch in ART is not defined. For the purposes of these guidelines,
virological failure is defined as a plasma HIV-1 RNA level above 10 000 copies/ml in a person
who has been on a regimen for more than six months and in whom drug adherence is determined
to be sufficient. This level has been chosen on the basis of the association of viral load levels
greater than 10 000 copies/ml with subsequent clinical progression 59 and appreciable CD4 cell
count decline.60
Virological success is defined as a plasma HIV-1 RNA level below the limit of detection of the
assay being used (e.g. values below 400 or below 50 copies/ml after six months of treatment).
An undetectable viral load mandates that ART should not, in general, be switched irrespective of
the CD4 cell count or the clinical stage.
Some programmes have established a local panel of experts to review cases under consideration
for second-line therapy for this reason. Clinical status, the CD4 cell count, and the plasma HIV-1
RNA level (if available) can be used in an integrated fashion to determine whether HIV disease is
progressing on therapy and whether a change from first-line to second-line therapy should be
made. Table 10 provides guidance on deciding when to switch the treatment regimen if clinical
status is considered in relation to the CD4 count alone or to the CD4 count plus viral load data.
Clinical judgement remains an important part of the decision-making process.
Treatment Failure
Who Stage 1 Who Stage 2 Who Stage 3 Who Stage 4
Criteria
39
10. Choice of second-line regimens
for treatment failure
WHO recommends that the entire regimen be changed if treatment failure occurs. The new
second-line regimen has to involve drugs that retain activity against the patient’s virus strain and
should ideally include a minimum of three active drugs, one of them drawn from at least one new
class, in order to increase the likelihood of treatment success and minimize the risk of cross-
resistance [A-III]. The PI class is thus reserved for second-line treatments, preferably supported
by two new NRTIs.
The key element in the construction of an effective second-line regimen for treatment failure is
the PI component, as this represents a potent drug from an entirely new (not previously used)
class of agents. Maximizing the potency of the PI component is critical for successful virological
suppression and durability of response. For this reason, a ritonavir-boosted PI (e.g. ATV/r, FPV/r,
IDV/r, LPV/r or SQV/r) is recommended as the core of the second-line regimen [A-II].
There are insufficient data on the differences between ritonavir-boosted PIs to allow the
recommendation of one agent over another. LPV/r has the advantage of being available as an
FDC; moreover, the recent approval of a heat-stable tablet formulation eliminates the need for
refrigeration. For other PIs to be boosted, ritonavir in heat-stable formulation is also desirable,
particularly in countries with hot climates, but it has not been developed. When a heat-stable
formulation becomes available or if the requirement for a cold chain is not a major issue for a
country programme, then any of a number of RTV-boosted PIs can be chosen. WHO recommends
that, if LPV/r is not an option, the alternative boosted PI be selected from SQV/r, ATV/r and FPV/r
[B-III]. IDV/r is effective but the incidence of nephrolithiasis and the daily fluid requirement make
this choice less attractive [C-II]. In the absence of a cold chain and in advance of the availability
of the new formulation of LPV/r, NFV is an acceptable alternative choice for the PI component,
although it is less potent than a boosted PI.61 62
Fig. 2 indicates the second-line strategies to be considered in adolescents and adults who
experience failure on the first-line regimens identified in Fig. 1
ddI or TDF
PI/r
1
EFV or NVP
NRTI-sparing option if triple NRTI
1 Ritonavir-boosted PIs (ATV/r, FPV/r, IDV/r, LPV/r and SQV/r) are considered as the key components in second-
line regimens and their use should be reserved for this situation. LPV/r is the only PI currently available as an
FDC and a new formulation that does not need refrigeration was recently launched. In the absence of a cold
chain and where the new LPV/r formulation is not available, NFV can be employed as the PI component but it is
considered less potent than an RTV-boosted PI.
2 3TC (± AZT) is included for strategic use as resistance to both drugs is predicted to be present following failure
on the respective first-line regimen listed. 3TC maintains the M184V mutation which may potentially decrease
viral replicative capacity as well as induce some degree of resensitization to AZT or TDF; AZT may prevent or
delay the emergence of the K65R mutation. It must be stressed that the clinical efficacy of this strategy in the
situation envisaged has not been proved.
The basic principle is ideally to support the chosen boosted PI with a dual NRTI backbone
composed of two unused NRTIs. Among the previously unused NRTIs, ddI is a key drug for the
construction of second-line regimens.63 It is available in different concentrations as buffered or
enteric-coated (EC) formulations. The buffered formulation is widely available and less costly.
However, it is frequently associated with diarrhoea and other gastrointestinal side-effects. The
EC formulation presents a better gastrointestinal tolerance, but is currently more expensive and
less available in resource-limited settings than buffered formulations. There are also limited data
on experience with the use of ddI EC formulations in these settings.
When failure has been identified clinically or immunologically, many patients can be expected to
have significant NRTI resistance at the time of switching. With respect to nucleoside class cross-
resistance and drug interactions, empirical alternative choices have to be made so as to provide
maximal antiviral activity. Cross-resistance exists between d4T and AZT, and second-line
regimens that offer more activity include ddI/ABC or TDF/ABC as dual NRTI components. The
41
issues of cost and drug hypersensitivity with ABC remain and high-level AZT/3TC resistance
confers diminished susceptibility to ABC. TDF can be compromised by multiple nucleoside
analogue mutations (NAMs) but often retains activity against nucleoside-resistant viral strains. It
should be noted that two of the recommended dual NRTI backbones in second-line regimens
(ddI/ABC and TDF/ABC) may facilitate the evolution of the K65R drug resistance mutation, which
mediates resistance to non-AZT NRTIs. Finally, the combination of TDF and ddI should be used
with caution because of suboptimal CD4 cell responses and increased toxicity with this dual
NRTI component.64 65 66 If this combination is used the ddI dose should be adjusted for body
weight in order to reduce the risks 67 68 69 (see Annex 3).
However some experts now recommend continuing 3TC in the setting of treatment failure
because it may confer a viral replicative defect and/or residual antiviral activity.70
10.3. Boosted PI/NNRTI for patients in whom first-line triple NRTI therapy fails
Two new classes of ARVs are available for constructing the second-line regimen in patients who
have had exposure only to NRTIs in the first-line regimen. The recommended combination is a
boosted PI plus an NNRTI with the option to add ddI and/or 3TC to the boosted PI/NNRTI
combination. Several studies have examined the NRTI-sparing approach of combining a boosted
PI and NNRTI. One study71 randomized 31 patients receiving standard therapy with two NRTIs
plus lopinavir (and with VL below 80 copies/ml) in order to continue this regimen or replace the
two NRTIs with NVP. At 48 weeks all patients maintained viral suppression. In a study in Thailand,72
60 patients in whom NRTI therapy failed were enrolled in a single-arm, open-label study of IDV/r
800 mg /100 mg twice a day plus EFV 600 mg once a day. The proportions of patients with
undetectable VL (below 50 copies/ml) at weeks 49 and 96 were 87% and 69% respectively.
Several groups and studies73 74 are evaluating strategies for simplifying or enhancing long- term
second-line therapy. The strategy of consolidating to boosted PI monotherapy following an initial
phase of three-drug therapy is under evaluation in treatment-naive patients, and the initial results
appear promising. The strategy has many similarities with standard TB treatment, with induction
followed by a maintenance phase; unlike TB treatment, however, ART does not have an end-
point representing cure. If the results continue to show promise, an induction/maintenance
approach may prove an important simplification strategy for long-term delivery and adherence
to second-line therapy, and this deserves further investigation. Additional studies are evaluating
a dual boosted PI approach to second-line ART for patients in whom there is failure of two
NRTIs/NNRTI. However, both approaches are at the stage of being investigated and neither
strategy is recommended.
Second-line regimen
First-line regimen
Rti component Pi component a
ddI + ABC or
AZT or d4T + 3TC b +
TDF + ABC or
NVP or EFV
TDF + 3TC (± AZT) c
Standard
TDF + 3TC b + ddI + ABC or
strategy
NVP or EFV ddI + 3TC (± AZT) c
PI/r d
43
11. Considerations for women of childbearing
potential or pregnant women
The guiding principle for treatment of women of childbearing potential or pregnant women is that
therapeutic decisions should be based solely on their need and eligibility for ART as outlined in
Section 5 [A-III]. The special circumstances of pregnancy and breastfeeding raise additional
issues of toxicity to mother and child, choice of ARV drug, and prevention of HIV transmission
from mother to child (PMTCT), but these concerns should be dealt with in the context of assuring
optimal treatment to preserve the mother’s health. Consequently, the recommended WHO first-
line regimen for this patient subgroup is an NVP-based scheme supported by two NRTIs. An
EFV-based regimen is suitable for women with access to consistent and reliable contraception
or for pregnant women after the first trimester of pregnancy who will have access to consistent
and reliable contraception in the postpartum period.
The choice of ART for women with the potential to become pregnant requires consideration of the
possibility that the ARV drugs may be received early in the first trimester, before recognition of
pregnancy and during the primary period of foetal organ development. The ARV drug of most
concern is EFV. Significant CNS defects have been observed in infant monkeys with in utero EFV
exposure at drug levels similar to those seen with human exposure at standard therapeutic doses,
and in four human infants with first trimester exposure to EFV-containing regimens.75 76 77 EFV should
therefore be avoided in women of childbearing potential who are not receiving adequate
contraception, because of possible teratogenicity [A-III]. Women who are receiving ART and do not
wish to become pregnant should have effective and appropriate contraceptive methods available
in order to reduce the likelihood of unintended pregnancy. In women for whom effective contraception
can be assured, EFV remains a viable option for the NNRTI component of the regimen.
While it may be desirable to initiate ART after the first trimester in order to minimize the potential for
teratogenicity, the benefit of early therapy clearly outweighs any potential foetal risks and therapy
should be initiated in such cases [A-IV]. Once started, ART should be continued postpartum.
• what is and is not known about the effects of the drugs on the pregnant woman and her infant
(including toxicity and teratogenicity) and about potential long-term effects of in utero
exposure on the child;
45
pregnant women. There are no data on the use of FTC in pregnancy, although data on other NRTI
drugs suggest that standard dosing would be appropriate. There are scant data on the use of TDF
during pregnancy. Studies in infant monkeys with in utero TDF exposure have not demonstrated
gross congenital abnormalities but have shown decreased fetal growth and a reduction in fetal
bone porosity within two months of the commencement of maternal therapy.80 Additionally, bone
demineralization has been observed in some infected children receiving chronic TDF-based
therapy.81 The clinical significance of these findings for children with in utero TDF exposure is
unknown. Because of the lack of data on use in human pregnancy and concern regarding potential
fetal bone effects, TDF should only be considered as a component of initial ART in pregnant women
if other alternatives are not available or are contraindicated [C-IV]. However, for a woman receiving
TDF who becomes pregnant the regimen may be continued; alternatively, AZT could be substituted
for TDF during the pregnancy [C-IV]. Additionally, for women receiving TDF because of toxicity or
resistance concerns related to other NRTI choices or as part of second-line therapy, the benefits of
continuing therapy outweigh theoretical risks of infant toxicity.
Studies in women in some, but not all, resource-constrained settings have suggested that the
risk of NVP-associated hepatic toxicity is lower than that reported in developed settings, and
have not noted an association between toxicity and CD4 counts. These studies have reported
grade 3 or grade 4 elevations in hepatic enzymes in 4% to 6% of women with a range of CD4 cell
counts. 92 93 94 95 96 97 In South Africa, however, higher rates of symptomatic severe hepatic toxicity
were found in women in a trial where CD4 counts were above 200 cells/mm 3 at entry (mean 398
cells/mm 3). 98 The numbers reported to date remain relatively low and further data are needed on
toxicity in different populations.
This creates a problem in respect of the treatment of women with CD4 counts between 250 and
350 cells/mm 3, for whom therapy is recommended if they are in WHO clinical stage 3. The exact
risk of fatal hepatitis with NVP in women in this CD4 count range is unclear, as the data have only
been presented for toxicity in approximately 200 women with CD4 counts in the range 250 to 399
cells/mm 3 in developed settings. Fatal symptomatic hepatitis was observed in 0.4% of women
with CD4 counts in this range; in contrast, mortality was highest, 1.1%, in women with CD4
counts exceeding 400 cells/mm 3. In the published case reports with data on CD4 counts, many
but not all of the women with symptomatic or fatal hepatic toxicity had CD4 counts above 350
cells/mm 3. There is probably a gradient of toxicity risk in women with CD4 counts above 250/
mm 3, with the greatest risk in women having a more normal immune status, as observed in
women without HIV infection who received NVP-based post-exposure prophylaxis. 99 100 Thus no
data are available allowing determination of the extent of risk of symptomatic or fatal hepatitis in
women with CD4 counts between 250 and 350 cells/mm 3.
The approaches to the treatment of women with CD4 counts between 250 and 350 cells/mm3
including the following: treating with NVP and maintaining close observation over the first 12 weeks
of therapy, as the benefit potentially could outweigh the risk; starting EFV and ensuring effective
contraception (although in a recent study of 548 women receiving EFV in Côte d’Ivoire the yearly
incidence of pregnancy was 2.6% despite counselling and the use of hormonal contraception);101
starting a triple NRTI regimen; delaying therapy until the CD4 count has fallen below 250 cells/
mm3; starting a PI-based regimen [C-IV]. Each of these approaches has advantages and
disadvantages (Table 11) and there are no data favouring one approach over any other. There is a
pressing need for better information about NVP toxicity in women and for research in this area.
47
If NVP-based therapy is initiated in women with CD4 counts between 250 and 350 cells/mm 3,
close monitoring is recommended during the first 12 weeks. This should include: education of
the patient on symptoms of concern, for which she should return to the clinic (e.g. rash, fever,
abdominal pain); more frequent visits in the first weeks of therapy (e.g. every two weeks);
evaluation of baseline liver enzymes and their frequent monitoring in the first 12 weeks (e.g.
baseline and at 2, 4, 8 and 12 weeks, followed by symptom-directed evaluation). If liver enzymes
increase to grade 3 or higher (ALT and/or AST exceeding 5.1 times the upper limit of normal)
without an alternative explanation, NVP should be permanently discontinued. NVP should be
discontinued immediately if any symptoms suggesting hepatic toxicity develop, including rash.
In this event it is vital not to wait until liver enzyme results are available.
Resistance to 3TC is also associated with a single mutation. In a study in which 3TC was added to
AZT therapy at 32 weeks of gestation in pregnant women in France, the 3TC resistance mutation
M184V was observed at six weeks postpartum in 39% of them;115 3TC resistance was also detected
at one week postpartum in 12% of women receiving AZT/3TC for four weeks in order to prevent
MTCT in the PETRA study.116 However, no AZT or 3TC resistance was observed with intrapartum
administration of AZT/3TC at one week postpartum.117
49
The clinical consequences of selection of these resistance mutations in terms of response to
future ART are unknown. A study in Thailand suggested that maximal viral suppression might be
decreased in women who had received single-dose NVP and subsequently initiated NVP-based
ART, although clinical and immunological responses did not differ from those where there was
no single-dose NVP exposure.118 The timing of initiation of NNRTI-based ART following single-
dose NVP exposure may be important: a lower rate of maximal viral suppression may occur if
ART is started less than six months after single-dose NVP exposure, whereas the response to
therapy appears to be the same as in women without single-dose NVP exposure if ART is started
six to eighteen months after exposure.119 Studies are in progress and planned with a view to
determining whether single-dose NVP prophylaxis compromises subsequent ART with NNRTI-
based regimens. This major operational research question must be answered with appropriately
conducted studies.
Until definitive data are available on these matters, women who have previously received single-
dose NVP prophylaxis for the prevention of MTCT should be considered eligible for NNRTI-
based regimens and should not be denied access to life-sustaining therapy. On the basis of
current data, a triple NRTI regimen, when available, can be considered as an alternative to
NNRTI-based therapy for initial treatment if ART is required to be started in women within six
months of single-dose NVP exposure [B-IV]. An initial PI-based regimen can also be considered
as an option in this situation, with the caveat that it then compromises the second-line treatment
options [C-IV]. The use of an NNRTI-based regimen is recommended for women with single-
dose NVP exposure who are initiating therapy more than six months after exposure [A-III].
The risk of drug resistance is strongly associated with the maternal plasma viral load and the
CD4 count at the time of exposure; consequently, the women most at risk of developing NVP
resistance with exposure to single-dose NVP are those with more advanced HIV disease for
whom the initiation of standard triple-drug combination therapy is recommended. One of the
best ways to prevent the development of NVP resistance is to assess the need of all pregnant
women for antiretroviral therapy, optimally including CD4 count evaluation, and to initiate
standard suppressive therapy for those who require it.
Tuberculosis is an important entry point into HIV care and a common opportunistic infection
among persons already diagnosed with HIV, particularly in resource-limited settings. HIV-
infected persons with TB often require ART, and WHO recommends that ART be given to all
patients with extrapulmonary TB (stage 4) and all those with pulmonary TB (stage 3) unless the
CD4 count is above 350 cells/mm 3. ART reduces both case-fatality rates and the incidence of TB
and recurrent TB.120 121
For patients with active TB in whom HIV infection is diagnosed and ART is required the first
priority is to initiate standard antituberculosis treatment (in accordance with national TB policy
and guidelines). The optimal time to initiate ART is not known. Case-fatality rates in patients with
TB during the first two months of TB treatment are high, particularly in settings where there are
high prevalences of HIV,124 suggesting that ART should begin early. On the other hand,
considerations of pill burden, drug-drug interactions, toxicity and IRIS support the later initiation
of ART.
While awaiting the results of current research studies, WHO recommends that, in persons with
CD4 cell counts below 200 cells/mm 3, ART should be started between two and eight weeks after
the start of TB therapy when the patient has stabilized on TB treatment [A-III]. This provisional
recommendation is meant to encourage rapid initiation of therapy in patients among whom there
may be a high mortality rate. For patients with CD4 cell counts above 200 cells/mm 3 the
commencement of ART may be delayed until after the initial intensive phase of TB treatment has
been completed, in order to simplify the management of TB treatment and to deal with the
challenges mentioned above [A-III]. In patients with CD4 counts above 350 cells/mm 3, ART can
be delayed until after the completion of short-course TB therapy, following a reassessment of the
patients eligibility for ART and evaluation of the response to TB therapy and of CD4 cell counts,
if available.
In circumstances where CD4 cell counts cannot be obtained, WHO recommends that ART be
initiated two to eight weeks after the start of TB therapy when the patient has stabilized on TB
treatment. For some patients with uncomplicated pulmonary TB disease in whom a good
response to TB therapy is seen, ART may be delayed until the initial intensive phase of TB
treatment is completed. ART may also be deferred in selected cases of extrapulmonary TB
(lymph node TB or patients with uncomplicated pleural disease) where a good response to TB
therapy is seen (Table 13) [A-IV].
51
Table 13. Initiating first-line ART in relationship to starting anti-TB therapy
The recommended standard first-line ART regimen comprises two NRTIs plus one NNRTI. There
are few drug interactions with TB drugs and the NRTI backbone and no specific changes are
recommended. The situation is more complex with the NNRTI class because NNRTI levels are
reduced in the presence of rifampicin. However, accumulating data support the use of first-line
NNRTI-containing antiretroviral regimens in patients receiving rifampicin-containing treatment
for TB. Here EFV is the preferred option, because the interactions with rifampicin are easier to
manage; but the use of EFV may be limited by its restrictions in pregnant women or women of
childbearing potential. NVP is an alternative agent, but carries the risk of hepatotoxicity,
particularly in persons with higher CD4 counts or for whom no CD4 count is available.125 The use
of a triple NRTI regimen is emerging as an additional option126 for first-line ART in TB patients with
HIV-2 infection. An initial PI-based regimen can also be considered in HIV-2 infection, with the
caveat that it will compromise second-line treatment options.
There are concerns about the risk of symptomatic or fatal hepatitis in women with CD4 counts
between 250 and 350 cells/mm 3. The additional influence on the liver toxicity of rifampicin-
containing regimens in this population is not known. Until further data are available, nevirapine-
containing regimens should only be considered in life-threatening situations and when no
alternative is available for women on rifampicin-containing regimens who have CD4 cell counts
in the range 250 to 350 cells/mm 3 and need to start ART.
An EFV-containing regimen is the first-line treatment recommendation for patients with TB and
HIV but should not be used during the first trimester of pregnancy or in women of childbearing
potential unless effective contraception is ensured. If a pregnant woman is in the second or third
trimester, an EFV-containing ART regimen can be considered. Effective contraception would
have to be assured postpartum if the regimen were continued. An alternative in women with
active TB is a triple NRTI regimen, e.g. AZT + 3TC + ABC. A change from an EFV-containing to
an NVP-containing regimen can be considered when TB treatment has been completed.
53
12.4. Immune reconstitution inflammatory syndrome in patients diagnosed
with TB who start ART
The immune reconstitution inflammatory syndrome (IRIS) may present as a worsening of clinical
disease after initial improvement. It may occur in up to a third of persons with tuberculosis who initiate
ART. IRIS typically presents within three months of the initiation of ART but can occur as early as five
days. TB-associated IRIS most commonly presents with fever and a worsening of pre-existing
lymphadenopathy or respiratory disease. It is similar to, but more frequent than, the paradoxical
reactions seen in immunocompetent patients on antituberculosis therapy. Several reports suggest
that IRIS is more common if ART is started early in the course of TB treatment and in patients with low
CD4 counts. Most cases resolve without any intervention and ART can be safely continued. Serious
reactions such as tracheal compression, caused by massive adenopathy, or respiratory difficulty,
may occur. Therapy may require the use of corticosteroids (see Section 5).137 138 139
There are two issues to consider in patients who are diagnosed with TB while on ART. The first
concerns the modifications of ART, if any, which should be recommended for patients developing
active TB within six months of initiating first-line or second-line ART. These recommendations are
summarized in Table 14.
• Substitute to EFV a b or
• Substitute to triple NRTI
First-line ART Two NRTIs + NVP regimen a or
• Continue with two NRTIs +
NVP c
Substitute to or continue ( if
already being taken) LPV/r- or
Second-line ART Two NRTI s + PI
SQV/r-containing regimen and
adjust dose of RTV a
a Substituting back to the original regimens once the rifampicin-containing regimen is completed can be
considered. When switching back from EFV to NVP, no lead-in dose is required.
b The use of EFV-containing regimens is not recommended in women of childbearing potential, if adequate
contraception cannot be ensured, and during the first trimester of pregnancy.
c Careful clinical and laboratory monitoring (ALT) is advised when NVP or boosted PIs are administered concurrently
with rifampicin.
WHO therefore recommends that the following principles be applied when determining whether
the development of TB on ART constitutes treatment failure. If an episode of TB occurs during
the first six months following the initiation of ART, this should not be considered a treatment
failure event (see Section 9) and the ART regimen should be adjusted for coadministration with
rifampicin-containing regimens [A-IV] (see Table 14).
If an episode of TB develops more than six months after the initiation of ART and data on the
CD4 cell count and viral load are available, the decision about whether the TB diagnosis
represents ART failure is based on the CD4 cell count and, if available, the viral load (see Section
9, Table 10). If a CD4 cell count is not available the decision on whether the TB diagnosis
constitutes ART failure depends on whether the TB is pulmonary or extrapulmonary and whether
there are other non-TB stage 3 or 4 events. While awaiting more data, WHO recommends that
the development of an episode of pulmonary TB after six months of ART, without other clinical
and immunological evidence of disease progression, should not be regarded as representing
ART failure. Extrapulmonary TB should be considered as indicating ART failure, although simple
lymph node TB or uncomplicated pleural disease may be less significant than disseminated TB.
If there is a good response to TB therapy the decision to switch to a second-line regimen can be
delayed until short-course TB therapy has been completed.
The effectiveness of second-line therapy for patients in whom an NNRTI regimen has failed
depends on the introduction of PIs in the new regimen. However, there are significant drug
interactions with the PIs and rifampicin. Consequently, the treatment options are constrained for
patients who develop TB while on PIs or for whom TB heralds the failure of a first-line regimen
(see above) and who require PI-based therapy.
Unboosted PIs cannot be used with rifampicin-containing regimens because protease inhibitor
levels are subtherapeutic [A-II].143 144
Thus, if a patient needs to switch to or is already on a PI-
based regimen, lopinavir 400 mg / ritonavir 400 mg twice daily in combination with rifampicin
could be considered under close clinical and laboratory monitoring to detect hepatic toxicity
[B-IV]. Full endorsement of this regimen requires further data. Alternatively, SQV 400 mg / RTV
400 mg can be considered, with the same close clinical and laboratory monitoring, but
endorsement of this PI-based regimen also requires further data [B-IV]. Concerns about the
55
combinations of SQV 1000 mg / r 100 mg b.d. with rifampicin include high rates of hepatic
toxicity reported in a study of HIV-uninfected volunteers and the potency of the combination. The
use of this and other boosted PI combinations is discouraged until further data are available.145
146 147 148
The recommendations and precautions for the use of PI-based regimens in combination with
rifampicin in women of childbearing potential and pregnant women are the same as for other TB
patients [B-IV].
When rifabutin is used in place of rifampicin, other boosted PIs regimens can be administered.
Dose adjustments are required in most situations and rifabutin is contraindicated in patients with
WBCs below 1000/mm 3 and platelet counts below 50 000/mm 3. Moreover, this drug can cause
uveitis. However, rifabutin may not be available or accessible in the public sector, and it is costly.
Efforts should be made to reduce its cost and increase its availability at country level.
HIV modifies the natural history of HBV infection: higher rates of progression to advanced liver
disease occur among persons with HIV/HBV coinfection.151 The presence of HIV infection is
associated with greater rates of progression to cirrhosis. The impact of HBV on the natural history
of HIV is less certain.152
In the setting of HIV infection the course of HCV-associated liver disease is accelerated. Rates
of progression of liver disease in HIV/HCV coinfection are greater.153 As with HBV, there is
contradictory evidence on the effects of HCV on HIV disease progression.154 155 156 157 In the Swiss
cohort study the presence of HCV was independently associated with an increased risk of
progression to AIDS and death. However, the EuroSIDA cohort analysis found that the overall
virological and immunological responses to ART were not affected by HCV serostatus. There
were no differences in the times needed to decrease viral loads to less than 400 copies or in the
times needed to increase CD4 cell counts by 50% between HCV-positive and HCV-negative HIV-
infected patients starting ART.158 However, the risk of mortality related to liver disease was
markedly increased in HCV-seropositive patients.159
Lamivudine (3TC) is efficacious against HBV in patients with and without HIV. The efficacy of 3TC
is limited by the occurrence of HBV drug resistance, which develops in 50% of patients after two
years of 3TC monotherapy for HBV and in 90% after four years of treatment.161 HBV seroconversion
(loss of HBeAg and development of HBe antibody) occurs in 11% to 22% of HBeAg-positive HIV-
1-infected patients who are treated with lamivudine for one year. The discontinuation of 3TC
without the inclusion of other anti-HBV drugs may be associated with hepatitis flares and rapid
clinical deterioration.
Emtricitabine (FTC) appears to have similar rates of suppression of HBV DNA, a similar safety
profile and a similar resistance pattern to those of 3TC.
57
Tenofovir (TDF) is effective against wild-type and 3TC-resistant HBV. On the basis of small
studies in HIV patients the efficacy of TDF against HBV appears superior to that of 3TC.162163
There is growing interest in the use of combination therapy for HBV with TDF and either 3TC or
FTC. The virological superiority of combination therapy with TDF and 3TC over monotherapy
with 3TC in both 3TC-naive and 3TC-experienced HIV-coinfected patients has recently been
demonstrated in preliminary studies.164 165
However, the impact of combination therapy on the
development of HBV resistance is currently under evaluation.
In situations where both HIV and HBV require treatment, the ART regimens must
contain 3TC and/or TDF. It is preferable to use 3TC and TDF together as both drugs
have anti-HIV and anti-HBV activity and the use of TDF or 3TC as the only anti-HBV
drug can result in more rapid development of resistance.
For treatment-naive HIV-1-infected persons who require ART, either 3TC at 150 mg twice daily or
300 mg daily or FTC at 200 mg daily is recommended for the treatment of chronic HBV infection
as part of the ART regimen. Because of the high rate of development of HBV resistance to 3TC
monotherapy, and because preliminary data have demonstrated a superior virological response
to combination therapy, the inclusion of TDF, where available, should be considered as part of
the ARV regimen. ARV programmes in areas of the world with a high HBV seroprevalence and no
capacity to screen for HBV may consider the use of TDF plus either FTC or 3TC as the preferred
initial NRTI combination. EFV is the preferred NNRTI option, or a triple NNRTI combination may
be used.
It is recommended that NVP be used with care and regular monitoring in patients who have
known HIV/HBV coinfection and grade 3 or lower elevation of ALT. NVP is not recommended for
those with ALT elevations of grade 4 or higher.
The initiation of ART in HIV/HCV-coinfected patients should follow the same principles and
recommendations as for the initiation of ART in HIV-monoinfected patients. However, the
patients should be followed up more closely because of the major risk of drug-related
hepatotoxicity and for specific drug interactions of some ARVs with anti-HCV drugs.
The major interactions are:
• Ribavirin and ddI –> pancreatitis/lactic acidosis (do not give concomitantly).
• Ribavirin and AZT –> anaemia (monitor closely).
• Interferon and EFV –> severe depression (monitor closely).
In patients with high CD4 cell counts it is preferable to treat HCV infection before HIV. While
concurrent treatment of both infections is feasible, it may be complicated by pill burden (RBV +
ARV drugs), drug toxicities and drug interactions. In patients who need ART it may be preferable
to initiate ART and delay HCV therapy in order to obtain better anti-HCV response rates after
immune recovery.
59
EFV is the NNRTI of choice in patients with HIV/HCV coinfection. A triple NRTI regimen is also an
option. It is recommended that NVP be used with care; if it is used in patients with HIV/HCV
coinfection who have grade 3 or lower elevation of ALT, regular monitoring is recommended.
NVP is not recommended in patients with ALT elevations of grade 4 or above.
The introduction of an EFV-containing regimen is recommended after the withdrawal of NVP (for
grade 4 ALT elevation and/or clinical hepatitis) and the stabilization of clinical status and ALT. If
EFV is withdrawn (for grade 4 ALT elevation and/or clinical hepatitis), NVP should not be initiated;
a triple NRTI regimen can be used.
The epidemiological importance of injecting drug use as a route of transmission of HIV varies
considerably between and even within countries. Worldwide, it is estimated that there are more
than 13 million injecting drug users (IDUs), the majority (about 80%) living in developing and
transitional countries.170 There are data indicating that IDUs may have lower and suboptimal
access to HIV care and may be less likely to receive antiretroviral therapy than other populations.171
172 173
In some settings, often in those countries where the HIV epidemic is largely driven by IDUs,
this arises because of a lack of provision of ART in general and to IDUs in particular.174 In settings
where ART is available, disordered lives, criminalization and social marginalization are the major
factors that adversely affect the provision of HIV care.173 174 Patients often present complicated
pictures to carers, involving psychiatric illness, coinfection with TB, HBV and HCV, high incidences
of bacterial infection, and polysubstance abuse. In addition, health care programmes often fail
to recognize that drug dependence is a medical condition and frequently have a perception that
drug users do not adhere to ART, overlooking the confounding effects of social instability,
poverty, psychiatric morbidity, human rights violations and poor patient-physician relationships
which characterize many drug users’ lives. The need to improve adherence among IDUs is
recognized but there is evidence suggesting that when engaged in stable care with experienced
staff and adequate support, IDUs can adhere to ART and have clinical outcomes comparable to
those of HIV patients who do not use drugs.173 175 Active drug use is therefore not a valid reason
for denying IDUs access to treatmen and care.
Thus, from the biomedical, epidemiological and ethical points of view, drug use should not be
used as an argument for withholding antiretroviral therapy from persons for whom treatment
would otherwise be recommended. A comprehensive approach to care and treatment of drug
dependence is recommended, but the absence of specific components (e.g. opioid substitution
treatment − OST) should not be a barrier to starting antiretroviral therapy in patients for whom it
is indicated.
61
Choice of ART in IDUs
• The basic WHO-recommended first-line and second-line drug formulary can be
used in selecting ART for the vast majority of IDUs [A-IV].
• The choice of specific antiretroviral drugs should also take into consideration that
the prevalence of hepatic, renal, neurological, psychiatric, gastrointestinal and
haematological comorbidities is higher in IDUs.
• Potential drug interactions with other legal or illicit drugs should be considered.
The criteria for initiating ART and the first-line and second-line therapies in substance-dependent
patients are the same as for the general population (see Sections 4 and 5).
The management of ART in IDUs may pose some challenges because of comorbidities, drug
side-effects and toxicities, the need for substance dependence treatment, drug interactions,
psychosocial problems and legal issues. Issues related to TB and viral hepatitis coinfection have
been dealt with in sections 12 and 13 respectively.
Support is needed such that IDUs can fully access available treatment services and adhere
strictly to treatment regimens. Adherence support should be part of the routine clinical care
provided by health professionals and peer support groups involved in dealing with HIV-positive
individuals.
The development of programmes that integrate care of drug dependence (including OST) and
HIV is therefore encouraged where approaches such as directly observed therapy (DOT) can be
considered. Harm reduction strategies are highly effective for IDUs in supporting HIV prevention,
treatment and care. Appropriate support, provided by an accessible and nonjudgemental health
care team and delivered through community-based programmes and outreach strategies, has
proved effective. Comprehensive harm reduction programmes also reduce new HIV infections
among IDUs.176 77
Whenever possible, preference should be given to antiretroviral regimens that include the drugs
least likely to cause hepatic, renal, haematological or neuropsychiatric side-effects. Simple
dosing schedules and the absence of interactions with, for example, methadone or buprenorphine,
are also desirable characteristics. The use of specific strategies (fixed-dose combinations,
once-daily drugs, directly supervised treatment, psychosocial support, case management)
should be strongly considered in order to improve adherence to treatment.
It is important to note that methadone and buprenorphine are now on the WHO Essential Drugs
List, a reflection of the world body’s commitment to the health rights of IDUs (http://www.who.
int/medicines/publications/essentialmedicines/en/index.html).
Methadone is the most commonly used replacement drug for the treatment of opiate dependence.
Since methadone interferes with gastric emptying and with metabolism by major cytochrome
P450 isoenzymes, interactions with ART are common and may lead to symptoms of opiate
withdrawal or overdose and/or to increased toxicity or to decreased efficacy of antiretroviral
drugs. From the perspective of ART provision, important drug interactions exist between some
ARVs and methadone, particularly the NNRTIs and certain PIs which can lower the levels of
methadone and precipitate withdrawal symptoms. The latter normally occur after several days of
coadministration and can be treated with stepwise increases in the daily doses of methadone.
The use of EFV or NVP is associated with significant decreases in methadone levels, which can
lead to opiate withdrawal symptoms. On the other hand, methadone does not affect NNRTI levels.
With regard to the PIs, the use of amprenavir, NFV or LPV can result in decreases in methadone
levels. NFV does not seem to be associated with opiate withdrawal but LPV/r has been associated
with opiate withdrawal symptoms. SQV and ATV do not seem to affect methadone levels. Except
for amprenavir, whose levels can be reduced by up to 30%, the available data indicate that the
use of methadone does not significantly affect PI levels. Although the pharmacokinetics of
methadone seem to be unaffected by NRTIs, methadone increases the area under the curve of
AZT by 40%, which in turn may lead to a higher incidence of AZT-related side-effects. Methadone
leads to a significant decline in levels of the buffered tablet formulation of ddI, but not of the
enteric-coated formulation. Interactions with other NRTIs are not likely to be clinically relevant.
Buprenorphine is increasingly used for the treatment of opiate dependence. There are limited
data on interactions with antiretroviral drugs. However, it appears that AZT in conjunction with
buprenorphine does not increase AZT levels as is the case with methadone. Interactions with
EFV, LPV/r and NFV can occur but do not seem to be clinically significant178 179 [A-III].
Annex 5 lists the major interactions between ARVs and methadone and buprenorphine.
Although HIV infection is most commonly associated with people who inject opiates, effective
treatment options for dependence on other substances, e.g. cocaine and amphetamine-type
stimulants (ATSs), should also be provided. At present there is no proven substitution therapy for
stimulant injectors. Interventions that have been shown to be beneficial in the treatment of
cocaine and ATS use and dependence include psychological interventions, cognitive behavioural
therapy (CBT), the community reinforcement approach, contingency management and twelve-
step programmes.
63
Challenges faced in the provision of ART to cocaine and ATS injectors are similar to those facing
services dealing with opioid injectors. Special efforts to reinforce ART adherence should also be
considered in this population.
In resource-limited settings, WHO recommends that clinical assessment be the primary tool for
monitoring patients, both before the initiation of ART and after it has started. However, it is highly
desirable to develop a laboratory monitoring protocol on a countrywide basis in order to improve
the efficacy of therapeutic interventions and to ensure the maximum level of safety when ARV
drugs are being delivered.
Clinical and laboratory monitoring of HIV-infected patients serves two purposes. Firstly, for
patients under care who are not yet eligible for ART, regular monitoring is essential for the
identification of the point at which they become eligible for ART or for prophylaxis against
opportunistic infections (e.g. with co-trimoxazole). Well-designed monitoring protocols can
facilitate the initiation of OI prophylaxis and ART in the majority of HIV-infected patients before
they develop advanced HIV infection.
Secondly, once patients have been initiated on ART, regular monitoring is necessary to assess
efficacy, manage side-effects and identify treatment failure. Regular monitoring is also essential
for reinforcing ARV adherence, the most critical parameter in the success of ART programmes.
Because resources are limited, laboratory testing should generally be directed by signs and
symptoms and should be done only when the results can be used to guide management
decisions. Exceptions are the recommendations to obtain a CD4 cell count every six months
[A-IV] and routine monitoring of haemoglobin in patients receiving AZT. Haemoglobin
measurement is recommended before the initiation of AZT and at 4, 8 and 12 weeks on AZT
treatment [A-IV].
• when to substitute one therapy for another because of significant side-effects (see Section 7);
• when to stop therapy and move to end-of-life and palliative care (see Section 17).
65
15.1. Baseline clinical and laboratory assessment
Every patient diagnosed as having HIV infection should undergo a baseline clinical and laboratory
assessment in order to determine the stage of HIV infection and eligibility for co-trimoxazole,
ART and other interventions. The baseline assessment should be used to evaluate patients for
the presence of active OIs, especially TB, and to serve as an entry point into chronic care. This
assessment should also serve as a means to provide counselling and support in relation to
secondary HIV prevention and the disclosure of HIV diagnosis to others.
15.2. Monitoring of patients who are not yet eligible for ART
Patients who are not yet eligible for ART should be monitored for clinical progression and by
CD4 count measurement every six months. Clinical evaluation should include the same
parameters as are used in baseline evaluations, including weight gain or loss and development
of clinical signs and symptoms of progressive HIV disease. These clinical parameters and the
CD4 cell count should be used to update the WHO disease stage at each visit and to determine
whether patients have become eligible for co-trimoxazole prophylaxis or ART. Clinical evaluation
and CD4 counts can be obtained more frequently as the clinical or immunological threshold for
initiating ART approaches (Table 4).
The frequency of clinical monitoring depends on the response to ART. At the minimum, however,
such monitoring should take place 2, 4, 8, 12 and 24 weeks after ART begins and should
subsequently be performed every six months once the patient has stabilized on therapy [A-IV].
At each visit, contact with a member of the health care team trained to triage is recommended,
with referral to a physician as needed. Many programmes dispense ART on a monthly basis,
thus increasing the number of opportunities to monitor clinical progression or drug toxicity.
Once ART is in progress, clinical assessment at each visit is the same as for pre-ART (except for
confirmation of HIV status), with the addition of counselling to assist the patient’s understanding
of ART and adherence support. Observation of the patient’s response to therapy should also
include assessment of symptoms of potential drug toxicities or treatment failure (i.e. reassessment
of clinical stage). Particularly important signs of a patient’s response to ART include a decreased
frequency of infections (bacterial infections, oral thrush, and/or other opportunistic infections).
Routine monitoring of CD4 cell counts (if available) is recommended every six months, or more
frequently if clinically indicated. The TLC is not suitable for monitoring therapy as a change in the
TLC value does not reliably predict treatment success.
Hyperlactataemia and lactic acidosis can develop in some patients on NRTIs. It is recommended
that the capacity to measure serum lactate be available at district or central laboratory level,
especially for patients receiving d4T or ddI. Routine measurements of serum lactate are not
useful in predicting the development of lactic acidosis. Serum lactate should only be measured
when patients have signs or symptoms suggesting lactic acidosis [B-IV].
Protease inhibitors can adversely affect glucose and lipid metabolism. Some experts support
routine monitoring of chemistry panels in patients receiving PI-based regimens. While such
monitoring may be advisable for specific patients receiving protease inhibitors, the laboratory
monitoring of lipids and glucose should generally take place in response to clinical symptoms
and signs.
In settings where serum lactate is not available, calculating the anion gap (anion gap = [Na + K] – [HCO3 + Cl], normal
6−12 mmol/l) is an alternative.
67
HIV viral load measurement is currently not recommended for monitoring patients on ART in
resource-limited settings [B-IV]. The use of viral load testing should be considered primarily for
the diagnosis of HIV infection in HIV-exposed infants aged under 18 months [B-I]. In adults and
adolescents, viral load testing may contribute to the diagnosis of ART failure earlier than would
happen if only clinical and CD4 monitoring were in place and in more complex cases, such as
those with discordant clinical and immunological responses (see Section 9, Table 10) [B-IV]
At initiation
Diagnosis and Pre-art* Every As required
of first-line or
monitoring (At entry six (Depending
second-line arv
laboratory tests into care) months on symptoms)
regimen
HIV diagnostic testing ¸ - -
Haemoglobin a ¸ - ¸
WBC and
- ¸ - ¸
differential b
Viral load
- - - ¸
measurement g
a Haemoglobin monitoring for patients on AZT is recommended at baseline and at weeks 4, 8 and 12 after
initiation of AZT.
b Monitoring at week 4, 8 and 12 after initiation of ART is optional.
c Patients who are not yet eligible for ART should be monitored with measurement of CD4 every six months. For
patients who develop WHO stage 2 events, or whose CD4 measurements approach threshold values, the
frequency of CD4 measurement can be increased. Patients on ART should have CD4 measurement every six
months if stable. More frequent CD4 monitoring may be necessary for deciding when to start or switch ART.
d Pregnancy testing for women initiating a first-line regimen containing EFV, and if pregnancy is suspected in
women who are receiving an EFV-based regimen.
69
16. Adherence to antiretroviral therapy
Particularly in the absence of HIV-RNA (viral load) for detecting early ART failure, adherence is
even more crucial for delaying or avoiding the development of drug resistance and ensuring
maximum durability of the first-line ARV regimen.
The contribution of dose timing is less well studied. A recent study demonstrated that a mean
dose-timing error (DTE) of less than three hours over a one-month period was independently
associated with virological suppression.184
A review of the efficacy of 24 adherence intervention studies published between 1996 and 2004
revealed that interventions targeting people with poor ART adherence had better outcomes. The
most frequently reported interventions in this review were reminder systems and counselling
support.185
The success of any adherence strategy depends on the education of patients before the initiation
of ART, an assessment of their understanding of the therapy, and their readiness for treatment.
Adherence counselling includes giving basic information on HIV and its manifestations, the
benefits and side-effects of ARV medications, how the medications should be taken and the
importance of not missing any doses. Peer counsellors and visual materials can be particularly
useful in this process.
Once treatment has begun the keys to success include trying to minimize the number of pills (in
part through the use of FDCs), the packaging of pills (coblister packs when available), the
frequency of dosing (no more than twice-daily regimens), the avoidance of food restrictions,
fitting the ARVs into the patient’s lifestyle, and the involvement of relatives, friends and/or
community members in supporting the patient’s adherence.
• Medications should be provided free of charge for people who can least afford treatment,
through subsidized or other financing strategies. Free access to ARVs at the point of delivery
may assist adherence.186 Recent data from Botswana, Senegal and other African countries
indicate that cost-sharing is detrimental to long-term adherence.187 188 These issues need
further exploration.
• Family-based care is desirable if more than one family member is HIV-infected. This is
particularly true when mother and child are infected.
• Directly observed therapy (DOT) or modified DOT strategies can be adopted. This approach
is resource-intensive and difficult to introduce on a large scale and for the lifelong duration
of ART. However, it may be helpful for certain groups (IDUs) and for early patient training.
At the programmatic level it is vital to ensure adequate stocks and storage of ARVs and to provide
necessary resources for culturally appropriate adherence counselling.
Adherence in women in the postpartum period may be particularly problematic and require
special support for them, as the stresses of caring for a newborn baby may lead a woman to pay
insufficient attention to her own health care.
Adherence in children is a special challenge, particularly if the family unit is disrupted by health,
economic or political conditions. Family-based HIV care programmes are some of the best
approaches to assuring childhood health. It is imperative that paediatric formulations be
improved and made widely available. They should match the adult regimens, where possible, so
that family-based care can be pursued effectively.
71
17. Heavily treatment-experienced patients
and when to stop ART
These guidelines detail a public health approach to ART and consider only first-line and second-
line antiretroviral regimens using the three different oral ARV classes of drugs. However, as
programmes mature and greater penetration of antiretrovirals into populations becomes a reality
there will be increasing numbers of patients who start to fail second-line therapies. Third-line,
fourth-line and fifth-line therapies are a reality in industrialized countries, where there are
possibilities for individualized patient management, routine viral load and drug resistance
testing, and access to the full formulary of licensed ARVs.
For patients who start to experience treatment failure on a second-line regimen with no further
treatment options, the failing ART regimen should be continued unless toxicities or drug
interactions are making the clinical situation worse for the patient [B-IV]. Even with treatment
failure the regimen is likely to have residual antiviral activity, and drug resistance mutations may
confer a replicative defect in the virus, possibly restricting its fitness and pathogenicity to some
extent. The M184V mutation associated with 3TC/FTC and the PI-associated mutations are most
frequently linked to such effects. The discontinuance of therapy in the setting of virological failure
can be associated with precipitous falls in CD4 cell counts and the occurrence of opportunistic
complications.
If a patient has exhausted all available antiretroviral and OI treatment options and is clearly in a
terminal condition because of advanced HIV infection or has distressing or intolerable side-
effects of therapy, it becomes reasonable to stop giving ARVs and to institute an active palliative
and end-of-life care plan.
Salvage options after a clinical failure of second-line ART are difficult to construct at the
population level if all three available oral ARV classes have been fully used. For highly treatment-
experienced patients, individual management is necessarily tailored to the availability of
alternative ARVs, for which there is very limited provision in the public sector in resource-limited
settings, and to additional laboratory investigations, such as individual drug resistance testing.
If and when new ARVs emerge, salvage may be feasible. Work on drug development must take
into consideration the needs of patients failing ART in resource-limited settings.
The expansion of ART programmes will inevitably be accompanied by the emergence of HIV
drug resistance (HIVDR), which has occurred in all countries where antiretroviral therapy is
routinely practised. The rapid or uncontrolled emergence of HIVDR is feared as a potential
consequence of ART scale-up in resource-limited countries.189
Several factors may limit efforts to prevent the emergence of drug resistance in such countries.
Given that switching from a first-line regimen to a second-line regimen is likely to be based on
clinical failure, some patients will have experienced drug pressure with high rates of viral
replication for periods ranging from days to months, and may have high levels of resistance to
some drugs and drug classes in the first-line regimen. As second-line regimens become
available it is important that information be available on a population basis to guide the selection
of the best NRTIs to support the PI class in second-line regimens for particular countries. Other
factors may also increase the risk of resistance emerging, including limited numbers of trained
health workers and facilities, and difficulties in drug supply continuity that may accompany rapid
expansion. However, other aspects of treatment programmes in resource-limited countries may
limit the risk. ART can be delivered successfully through the national implementation of rational
ART guidelines on the basis of the “three ones” principles190 (one agreed HIV/AIDS action
framework for coordination, one national AIDS coordinating authority, and one agreed country-
level monitoring and evaluation system). The use of optimal simplified highly active first-line
combination regimens in resource-limited countries can support a high degree of viral
suppression on a population basis. The sequential use of regimens inadequate to suppress viral
replication is unlikely where publicly available first-line and second-line regimens are standardized
and frequently available as fixed-dose combinations. The availability of a limited number of
potent standardized regimens can limit aberrant prescribing practices and unnecessary regimen
switching. Finally, where public ART programmes are standardized and coordinated at national
level in resource-limited countries, large-scale changes to optimize programme practices can
be made relatively quickly. Efforts to ensure that evidence-based programme monitoring occurs
countrywide are based on a system developed by a large number of organizations and countries
for monitoring key treatment-related variables,191 many of which are directly relevant to evaluating
HIVDR prevention.
In addition to the general measures listed, WHO recommends that a specific strategy to evaluate
and limit HIVDR be included in all national HIV prevention and treatment plans. The objectives of
the WHO HIVDR strategy for countries are: (1) to use a standard methodology for regular
population-level evaluations of HIVDR emergence and transmission; (2) to implement ongoing
evaluation of ART programme factors potentially associated with HIVDR emergence; and (3) to
support evidence-based recommendations for maintaining the effectiveness of ART regimens
and limiting HIVDR transmission.
With a view to the development and implementation of the strategy, WHO HIVResNet, a global
network of over 50 HIVDR clinical, laboratory, epidemiological and research experts and
organizations, has been set up. Members support WHO and the genotyping laboratory network
in the development of protocols and guidelines, criteria and assessment tools, and the global
database. Members also assist WHO in providing technical assistance in countries for HIVDR
strategy implementation.
73
Preventing unnecessary emergence and transmission
of HIV drug resistance at the population level
WHO’s public health principles for minimizing HIVDR involve:
• fostering adherence;
• the formation of a national HIV drug resistance working group in each country, convened by
the ministry of health or the national AIDS committee, to plan and implement a coordinated
HIVDR prevention and evaluation strategy;
• surveillance of HIV drug resistance in order to assess transmitted drug resistance in newly
infected individuals in specific geographical areas of each country;
• surveys of HIVDR at sentinel ART sites and related ART programme factors;
Specific public health actions are recommended on the basis of the prevalence category for
resistance to the drugs and drug categories. The results can contribute to decision-making about
optimal ART regimens and prevention strategies based on the use of ART for pre-exposure and
post-exposure prophylaxis, and about the prevention of mother-to-child transmission of HIV.
A cohort of patients beginning first-line ART is evaluated at baseline and after 12 months, or at
an end-point occurring earlier than 12 months. An effective sample size of 96 is included at each
sentinel site. Because individuals beginning first-line ART in resource-limited settings may have
ARV drug experience or transmitted resistance, the evaluation includes a baseline sequence of
the relevant regions of the HIV pol gene and a history of ARV use, as well as recording initial
regimens and any changes. At the time of switching to a second-line regimen or at 12 months for
patients still on a first-line regimen (including substitutions), blood is collected for viral load
testing and HIVDR genotyping. Other end-points may be determined by loss to follow-up, death,
cessation of ART or transfer from one ART clinic to another. Since the HIVDR status of persons
who have died or been transferred cannot be assessed, the corresponding data are not
represented in the denominator and the numerator. For all evaluated individuals, standardized
adherence measures and the regularity of both appointment- keeping and ARV drug pick-up are
recorded. At the ART site level the continuity of drug supply is assessed.
The absence of HIVDR is defined as a suppressed viral load at the time of the second blood
sampling; if plasma viral load is detected, patterns of resistance are analysed. Factors potentially
associated with a lack of HIVDR prevention are recorded and analysed along with the outcomes.
These factors include previous ARV exposure, irregularities in appointment-keeping or drug pick-
75
up, ARV prescribing practices, and a lack of drug supply continuity at the site in question. The
association between patterns of resistance mutations and HIV-1 subtype are also evaluated if the
numbers are adequate. The results support recommendations for optimal first-line and second-
line regimens, indications for the time of regimen switching on a population basis, and specific
actions to improve outcomes at sentinel clinics.
Considerable progress has been made in the past four years towards making ART scale-up in
the developing world a reality. However, much remains to be done. For people on treatment we
must strive to make its benefits durable and sustainable. For people not yet on treatment but
requiring it, resources have to be mobilized and systems put in place so as to reach them. These
resources will be threatened by the high cost of drugs needed for moving to second-line
regimens or by the inclusion of new drugs in first-line regimens. Universal access may not
become a reality unless barriers to accessing all needed drugs are appropriately addressed.
We also cannot rest with the current formulary of available drugs as toxicities and drug resistance
will drive the need for new treatment options. Every possible effort should be made to decrease
the prices of these drugs as well as to ensure the production and use of the most adapted
formulations. Moreover, all necessary measures should be taken to accelerate registration on
approval for these products by national drug regulatory agencies, including fast-track approval
of those products already included in the WHO prequalification list, which is regularly updated.
There are immediate needs in the area of diagnostics. Making affordable and accurate CD4 cell
counting widely available is a high priority. Simultaneously, the field needs to move towards the
development and implementation of affordable viral load testing. CD4 and plasma HIV-1 RNA
testing are not luxuries. They are important tools supporting the delivery of optimal care and, in
the setting of the public health approach, are invaluable measures of programme monitoring
and performance. Clinical and operational research studies are crucial for providing the
information needed to inform programme managers and clinicians about the optimal approaches
to treating and monitoring HIV infection in resource-limited settings.
We hope the present edition of the WHO ART guidelines for adults and adolescents will be of
practical value to programme managers and carers today while helping to move the field forward
to reach more people in the near future and continuing to improve the standard of care for
millions of HIV-infected persons worldwide.
77
Annex 1. WHO clinical staging of HIV disease
in adults and adolescents
CLINICAL STAGE 1
Asymptomatic
Persistent generalized lymphadenopathy
CLINICAL STAGE 2
Unexplaineda moderate weight loss (under 10% of presumed or measured body weight)b
Recurrent upper respiratory tract infections (sinusitis, tonsillitis, otitis media, pharyngitis)
Herpes zoster
Angular cheilitis
Recurrent oral ulceration
Papular pruritic eruptions
Seborrhoeic dermatitis
Fungal nail infection
CLINICAL STAGE 3
Unexplained a severe weight loss (over 10% of presumed or measured body weight)b
Unexplained a chronic diarrhoea for longer than one month
Unexplained a persistent fever (intermittent or constant for longer than one month)
Persistent oral candidiasis
Oral hairy leukoplakia
Pulmonary tuberculosis (current)
Severe bacterial infections (e.g. pneumonia, empyema, pyomyositis, bone or joint infection,
meningitis, bacteraemia, severe pelvic inflamatory disease)
Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis
Unexplained a anaemia (below 8 g/dl ), neutropenia (below 0.5 x 10 9/l) and/or chronic
thrombocytopenia (below 50 x 10 9 /l)
Source: Revised WHO clinical staging and immunological classification of HIV and case definition of HIV for surveillance.
2006 (in press).
79
Annex 2. Criteria for HIV-related clinical events
in adults and adolescents
CLINICAL STAGE 2
Moderate unexplained Reported unexplained weight Documented weight loss
weight loss (under 10% of loss. In pregnancy, failure to (under 10% of body weight)
body weight) gain weight
Fungal nail infection Paronychia (painful red and Fungal culture of nail / nail
swollen nail bed) or plate material
onycholysis (separation of
nail from nail bed) of the
fingernails (white
discolouration, especially
involving proximal part of
nail plate, with thickening
and separation of nail from
nail bed)
CLINICAL STAGE 3
Severe unexplained weight Unexplained reported weight Documented loss of more
loss (more than 10% of body loss (over 10% of body than 10% of body weight
weight) weight) and visible thinning of
face, waist and extremities
with obvious wasting or body
mass index below 18.5. In
pregnancy, weight loss may
be masked.
81
Clinical event Clinical diagnosis Definitive diagnosis
Unexplained persistent fever Reports of fever or night Documented fever exceeding
(intermittent or constant and sweats for more than one 37.5 oC with negative blood
lasting for longer than one month, either intermittent or culture, negative Ziehl-
month) constant with reported lack of Nielsen (ZN) stain, negative
response to antibiotics or malaria slide, normal or
antimalarials, without other unchanged chest X-ray (CXR)
obvious foci of disease and no other obvious focus of
reported or found on infection
examination. Malaria must be
excluded in malarious areas.
CLINICAL STAGE 4
HIV wasting syndrome Unexplained involuntary weight Documented weight loss
loss (over 10% of body weight) (over 10% of body weight)
with obvious wasting or body plus
mass index below 18.5 two or more unformed stools
PLUS EITHER negative for pathogens
unexplained chronic diarrhoea or
(loose or watery stools three documented temperature
or more times daily) reported exceeding 37.6 oC with no
for longer than one month other cause of disease,
OR negative blood culture,
reports of fever or night sweats negative malaria slide and
for more than one month normal or unchanged CXR
without other cause and lack of
response to antibiotics or
antimalarials. Malaria must be
excluded in malarious areas.
83
Clinical event Clinical diagnosis Definitive diagnosis
Pneumocystis pneumonia Dyspnoea on exertion or Cytology or
nonproductive cough of immunofluorescent
recent onset (within the past microscopy of induced
three months), tachypnoea sputum or bronchoalveolar
and fever; AND CXR evidence lavage (BAL), or histology of
of diffuse bilateral interstitial lung tissue.
infiltrates, AND no evidence
of bacterial pneumonia,
bilateral crepitations on
auscultation with or without
reduced air entry.
Recurrent bacterial Current episode plus one or Positive culture or antigen test
pneumonia more episodes in last six of a compatible organism
(this episode plus one or months. Acute onset (under
more episodes in last six two weeks) of symptoms (e.g.
months) fever, cough, dyspnoea, and
chest pain) PLUS new
consolidation on clinical
examination or CXR.
Response to antibiotics.
Chronic herpes simplex virus Painful, progressive Positive culture or DNA (by
(HSV) infection (orolabial, anogenital or orolabial PCR) of HSV or compatible
genital or anorectal) of more ulceration; lesions caused by cytology/histology
than one month, or visceral of recurrent HSV infection and
any duration reported for more than one
month. History of previous
episodes. Visceral HSV
requires definitive diagnosis.
85
Clinical event Clinical diagnosis Definitive diagnosis
HIV encephalopathy Clinical finding of disabling Diagnosis of exclusion, and, if
cognitive and/or motor available, neuroimaging (CT
dysfunction interfering with or MRI)
activities of daily living,
progressing over weeks or
months in the absence of a
concurrent illness or
condition, other than HIV
infection, which might explain
the findings
87
Annex 3. Dosages of antiretroviral drugs
for adults and adolescents
Didanosine (ddI)
>60 kg: 400 mg once daily
Buffered tablets or enteric-coated
<60 kg: 250 mg once daily
(EC) capsules a
Nevirapine (NVP) 200 mg once daily for 14 days, followed by 200 mg twice
daily
PROTEASES INHIBITORS
Atazanavir + ritonavir (ATV/r) 300 mg +100 mg once daily
Treatment-naive patients
• Two tablets twice daily
Lopinavir/ritonavir (LPV/r) d
irrespective of
coadministration with
EFV or NVP (400/100
Tablets (heat-stable mg twice daily)
formulation)
Lopinavir 200 mg / Treatment-experienced
ritonavir 50 mg patients
• Three tablets twice
daily when combined
with EFV or NVP
(600/150 mg twice
daily)
a ddI dose should be adjusted when coadministered with tenofovir. If weight is above 60 kg the recommended dose
is 250 mg once daily. If weight is below 60 kg there are no data on which to base a recommendation (some
preliminary pK studies suggest 125−200 mg once daily).193 Buffered ddI should be taken on an empty stomach.
b Some experts recommend d4T at 30 mg for all patients irrespective of body weight.
c Other dose regimens in clinical use are 600 mg + 100 mg twice daily194 and 400 mg + 100 mg twice daily.195, 196, 197
d See Section 12 for TB-specific dose modifications of lopinavir/r and saquinavir + ritonavir.
89
Annex 4. Storage of antiretrovirals
Lopinavir/ritonavir (LPV/r)
Room temperature
heat-stable tablets
91
Annex 5. Drugs that interact
with antiretrovirals
ANTIFUNGAL
Ketoconazole ↑ ketoconazole level by 63%. No significant changes in
↑ NVP level by 15−30%. ketoconazole or EFV levels
Do not recommend
coadministration.
ANTIFUNGAL
↑ LPV AUC. No dose adjustment ↑ SQV level threefold.
↑ ketoconazole level necessary No dose adjustment
threefold. necessary if given unboosted.
Do not exceed 200 mg/day For RTV-boosted SQV – no
ketoconazole. data (RTV treatment dose can
increase ketoconazole level
threefold).
93
ARVs NVP EFV
Fluconazole ↑ NVP Cmax, AUC, Cmin by No data
100%.
No change in fluconazole
level.
Possible increase in
hepatotoxicity with
coadministration requiring
monitoring of NVP toxicity.
ORAL CONTRACEPTIVES
Ethinyl estradiol ↓ ethinyl estradiol by 20%. ↑ ethinyl estradiol by 37%.
Use alternative or additional Use alternative or additional
methods. methods.
ANTICONVULSANTS
Carbamazepine Use with caution. One case Unknown. Use with caution.
Phenytoin report showed low EFV
concentrations with
phenytoin.
↓ ethinyl estradiol level by ↓ norethindrone level by 18%. No data for unboosted SQV.
42%. Use alternative or ↓ ethinyl estradiol level by RTV treatment dose can ↓
additional methods. 47%. level of ethinyl estradiol by
41%.
Many possible interactions. Unknown, but may decrease Unknown, but may markedly
Carbamazepine: ↑ levels NFV levels substantially. reduce SQV levels.
when coadministered Monitor anticonvulsant levels Monitor anticonvulsant levels
with RTV. Use with caution. and virological response. and consider obtaining SQV
Monitor anticonvulsant levels. level.
Phenytoin: ↓ levels of LPV
and RTV, and ↓ levels of
phenytoin when administered
together.
Avoid concomitant use or
monitor LPV level.
95
ARVs NVP EFV
OPIOID SUBSTITUTION TREATMENT
Methadone Levels: NVP unchanged. Levels: methadone ↓ 60%.
Methadone ↓ significantly. Opiate withdrawal common,
Opiate withdrawal common increase in
when this combination is methadone dose often
used. Increased methadone necessary. Titrate
dose often necessary. Titrate methadone dose to effect.
methadone dose to effect.
LIPID-LOWERING AGENTS
Simvastatin, Lovastatin No data ↓ simvastatin level by 58%.
EFV level unchanged.
Adjust simvastatin dose
according to lipid response;
not to exceed the maximum
recommended dose.
Methadone AUC ↓ 53%. NFV may decrease Methadone AUC ↓ 20% when
Opiate withdrawal may occur. methadone levels, but opiate coadministered with SQV/RTV
Monitor and titrate dose if withdrawal 400/400
needed. May require increase rarely occurs. Monitor and mg b.d. No adjustment for
in methadone dose. titrate dose if needed. May this PI regimen, but monitor
require increase in and titrate to methadone
methadone dose. response as necessary.
Potential large ↑ statin level. ↑ simvastatin AUC by 505%. Potential large ↑ statin level.
Avoid concomitant use. Potential large ↑ lovastatin Avoid concomitant use.
AUC.
Avoid concomitant use.
↑ atorvastatin AUC 5.88 fold. ↑ atorvastatin AUC 74%. ↑ atorvastatin level by 450%
Use lowest possible starting Use lowest possible starting when used as SQV/RTV.
dose with careful monitoring. dose with careful monitoring. Use lowest possible starting
dose with careful monitoring.
97
ARVs NVP EFV
ANTICONVULSANTS
Carbamazepine, Unknown. Use with caution. Use with caution. One
Phenobarbital, Phenytoin Monitor anticonvulsant case report showed low
levels. EFV levels with phenytoin.
Monitor anticonvulsant and
EFV levels.
Proton pump inhibitors. All the PIs and EFV can increase levels of cisapride and non-sedating
antihistamines (aztemizole, terfenedine), which can cause cardiac toxicity.
Coadministration is not recommended.
↑ carbamazepine from RTV. Unknown but may decrease Unknown for unboosted SQV
Both phenytoin and LPV/r NFV level substantially. but may markedly ↓ SQV
levels ↓. For all, avoid Monitor NFV/anticonvulsant level.
concomitant use or monitor levels. Monitor SQV/anticonvulsant
LPV/anticonvulsant levels. levels.
Proton pump inhibitors. All the PIs and EFV can increase levels of cisapride and non-sedating
antihistamines (aztemizole, terfenedine), which can cause cardiac toxicity.
Coadministration is not recommended.
99
Annex 6. Tiered laboratory capabilities for ART
monitoring in resource-limited settings
Regional/
Diagnosis and monitoring Primary District
referral
laboratory tests care level level
level
HIV antibody testing a
¸ ¸ ¸
Haemoglobin c + ¸ ¸
Pregnancy testing d + ¸ ¸
ALT - ¸ ¸
101
Annex 7. Severity grading of selected clinical
and laboratory toxicities
(Source: Division of AIDS, National Institute of Allergy and Infectious Diseases, USA − modified.)
For abnormalities NOT found elsewhere in the toxicity table use the scale below to estimate
grades of toxicity.
GRADE 2 Mild to moderate limitation of activity; some assistance may be needed; no or minimal
medical intervention/therapy required.
GRADE 3 Marked limitation of activity; some assistance usually required; medical intervention/
therapy required; hospitalization possible.
Hypokalaemia 3.0 − 3.4 2.5 − 2.9 2.0 − 2.4 meq/ <2.0 meq/l
meq/l OR 3.0 meq/l OR 2.5 l OR 2.0 − 2.4 OR <2.0
− 3.4 mmol/l − 2.9 mmol/l mmol/l mmol/l
BILIRUBIN
Hyperbilirubin- >1.0 − 1.5 x >1.5 − 2.5 x >2.5 − 5 x >5 x ULN
aemia ULN ULN ULN
GLUCOSE
Hypoglycaemia 55 − 64 mg/dl 40 − 54 mg/dl 30 − 39 mg/dl <30 mg/dl OR
OR 3.01 − OR 2.19 − OR 1.67 − <1.67 mmol/l
3.55 mmol/l 3.00 mmol/l 2.18 mmol/l
Hyperglycaemia 116 − 160 161 − 250 mg/ 251 − 500 mg/ >500 mg/dl
(nonfasting and no mg/dl OR 6.44 dl OR 8.91 − dl OR 13.89 − OR >27.76
prior diabetes) − 8.90 mmol/l 13.88 mmol/l 27.76 mmol/l mmol/l
TRANSAMINASES
AST (SGOT) 1.25 − 2.5 x >2.5 − 5.0 x >5.0 − 10.0 x >10.0 x ULN
ULN ULN ULN
ALT (SGPT) 1.25 − 2.5 x >2.5 − 5.0 x >5.0 − 10.0 x >10.0 x ULN
ULN ULN ULN
103
Chemistries Grade 1 Grade 2 Grade 3 Grade 4
TRANSAMINASES
Pancreatic enzymes
Pancreatic amylase >1.0 − 1.5 x >1.5 − 2.0 x >2.0 − 5.0 x >5.0 x ULN
ULN ULN ULN
105
Miscellaneous Grade 1 Grade 2 Grade 3 Grade 4
Fatigue Normal Normal Normal activity Unable to
activity activity reduced by care for self
reduced by reduced by >50%; cannot
<25% 25−50% work
GI intolerance, with taste All ARVs (less Usually self-limited, without need to
changes, nausea, vomiting, frequent with discontinue ART. Symptomatic treatment
abdominal pain and d4T, 3TC, FTC should be offered.
diarrhoea. and ABC)
107
Adverse effect Major ARVs Recommendations
Hepatitis All ARVs Intense elevations of ALT associated with
(particularly clinical features have been described with
with NVP NVP; however, changes of varying intensity
and ritonavir- may be observed with all ARVs, mediated
boosted PIs) by different mechanisms.
If ALT is at more than five times the basal
level, discontinue ART and monitor. After
resolution, replace the drug most likely
associated with the condition.
Renal toxicity ( renal tubular TDF Discontinue TDF and give supportive
dysfunction) treatment. After clinical resolution, resume
ART, replacing the offending drug.
109
Annex 9. Sexual maturity rating (Tanner staging)
Female
Stage
Age Breast growth Pubic hair Other changes
range growth
(years)
I 0 − 15 Pre-adolescent None Pre-adolescent
111
Annex 10. (coformulations
Currently available fixed-dose combinations
and coblister packs) of antiretrovirals
a b
LPV/r (co-formulation)
a Co-formulations are based on the principle of inclusion of two or more active pharmacological products in the
same capsule, tablet or solution.
b Blister packs is defined a plastic or aluminium blister containing two or more capsules or tablets.
2 Beck EJ, Vitoria M, Mandhalia S, et al. National adult antiretroviral therapy guidelines in
resource-limited countries: concordance with 2003 WHO guidelines? AIDS 2006;20:1497-
502.
3 Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.
2006. http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines
&Search=Off&GuidelineID=7&ClassID=1
4 The British HIV Association. BHIVA guidelines for the treatment of HIV-infected adults with
antiretroviral therapy 2005.. HIV Medicine 2005;6(Suppl 2):1-61. http://www.bhiva.org/
guidelines/2005/HIV/HIV05frameset.htmlb
5 Egger M, May M, Chene G, et al. Prognosis of HIV1-infected patients starting highly active
antiretroviral therapy: a collaborative analysis of prospective studies. Lancet
2002;360(9327):119-29.
6 Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine
in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N
Engl J Med 1997;337(11):734-9.
7 Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues
plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts
of 200 per cubic millimeter or less. N Engl J Med 1997;337(11):725-33.
8 Garcia F, De Lazzari E, Plana M, et al. Long-term CD4+ T-cell response to highly active
antiretroviral therapy according to baseline CD4+ T-cell count. JAIDS 2004;36(2):702-13.
10 Wood E, Hogg RS, Harrigan PR, Montaner JSG. When to initiate antiretroviral therapy in HIV-1
infected adults: a review for clinicians and patients. Lancet Infect Dis 2005;5:407-14.
13 Saag MS. Emtricitabine, a new antiretroviral agent with activity against HIV and hepatitis B
virus. Clin Infect Dis 2006;42(1):126-31.
14 Jones R, Stebbing J, Nelson M, et al. Renal dysfunction with tenofovir disoproxil fumarate-
containing highly active antiretroviral therapy regimens is not observed more frequently. A
cohort and case-control study. JAIDS 2004;37(4):1489-95.
113
15 Izzedine H, Hulot JS, Vittecoq D, et al, and Study 903 Team. Long term renal safety of
tenofovir disoproxil fumarate in antiretroviral naive HIV-1-infected patients. Data from a
double blind randomized active-controlled multicentre study. Nephrol Dial Transplant
2005;20:743-6.
18 van Leth F, Phanuphak P, Ruxrungtham K, et al, for the 2NN Study Team. Comparison of
first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs,
plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet
2004;363(9417):1253-63.
20 Gulick R, Ribaudo H, for the AIDS Clinical Trials Group Study A5095 Team. Triple-nucleoside
regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection.
New Eng J. Med 2004;350:1850-61.
21 DART Virology Group and Trial Team. Virological response to a triple nucleoside/nucleotide
analogue regimen over 48 weeks in HIV-1 infected adults in Africa. AIDS 2006, 20:1391-9.
22 Gallant JE, Rodriguez AE, Winkler G, et al, and the ESSS3009 Study. Early virologic non-
response to tenofovir, abacavir and lamivudine in HIV-infected antiretroviral-naive subjects.
J Inf Dis 2005;192(11):1921-30.
24 Ssali F, Stöhr W, Munderi P, Reid A, Walker AS, Gibb DM, et al, and the DART Trial Team.
Incidence, predictors and timing of severe anaemia following initiation of zidovudine-
containing regimens in adults with HIV infection in Africa within the DART Trial. Antiviral Ther
2006 (in press).
29 Costello C, Nelson K, et al. Predictors of low CD4 count in resource-limited settings based
on an antiretroviral-naive heterosexual Thai population. JAIDS 2005;39:242-8.
31 French MA, Lenzo N, John M, et al. Immune restoration disease after the treatment of
immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Med
2000;1:107-15.
32 Breen RAM, Smith CJ, Bettinson H, et al. Paradoxical reactions during tuberculosis
treatment in patients with and without HIV co-infection. Thorax 2004;59:704-7.
33 Shelburne S, Visnegarwala F, Darcourt J, et al. Incidence and risk factors for immune
reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005;
9:399-406.
35 Shelburne SA, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory
syndrome: emergence of a unique syndrome during highly active antiretroviral therapy.
Medicine (Baltimore) 2002;81:213–27.
36 Lipman M, Breen R. Immune reconstitution inflammatory syndrome in HIV. Curr Opin Infect
Dis 2006;19:20-5.
39 Shelburne SA, Hamill RJ. The immune reconstitution inflammatory syndrome. AIDS Rev
2003;5:67-79.
115
41 Kumarasamy N, Vallabhaneni SJ, et al. Reasons for modification of generic highly active
antiretroviral therapeutic regimens among patients in southern India. JAIDS 2006;41(1):53-
8.
43 Friis-Moller N, Weber R, et al, for the DAD Study Group. Cardiovascular disease risk factors
in HIV patients − association with antiretroviral therapy. Results from the DAD study. AIDS
2003;17(8):1179-93.
44 Ivers LC, Mukherjee JS. Point of care testing for antiretroviral therapy-related lactic acidosis
in resource-poor settings. AIDS 2006;20(5):779-80.
45 Palella FJ, Cole SR, Chmiel JS, et al. Anthropometrics and examiner-reported body habitus
abnormalities in the multicenter AIDS cohort study. Clin Infect Dis 2004;38:903-7.
46 John M, Nolan D, Mallal S. Antiretroviral therapy and the lipodystrophy syndrome. Antivir
Ther 2001;6:9-20.
47 Joly V, Flandre P, Meiffredy V, et al. Increased risk of lipoatrophy under stavudine in HIV-1-
infected patients: results of a substudy from a comparative trial. AIDS 2002;16:2447-54.
48 Mallon PW, Miller J, Cooper DA, Carr A. Prospective evaluation of the effects of antiretroviral
therapy on body composition in HIV-1-infected men starting therapy. AIDS 2003;17:971-9.
50 Johnson AA, Ray AS, Hanes J, et al. Toxicity of antiviral nucleoside analogs and the human
mitochondrial DNA polymerase. J Biol Chem 2001;276:40847-57.
53 Ledergerber B, et al. Predictors of trend in CD4-positive T-cell count and mortality among
HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes.
Lancet 2004;364(9428):51-62.
55 Kousignian I, et al. Modeling the time course of CD4 T-lymphocyte counts according to the
56 Murri R, et al. Is moderate HIV viremia associated with a higher risk of clinical progression in
HIV-infected people treated with highly active antiretroviral therapy: evidence from the Italian
cohort of antiretroviral-naive patients study. JAIDS 2006;41(1):23-30.
57 Gadelha A, Accacio N. Morbidity and survival in advanced AIDS In Rio de Janeiro, Brazil.
Rev Inst. Trop S Paulo 2002;449:179-86.
58 Mellors J, Munoz A, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers
of HIV-1 infection. Ann Intern Med 1997;126(12):946-54.
59 Murri R, Lepri AC, et al, for the ICONA Study Group. Is moderate HIV viraemia associated
with a higher risk of clinical progression in HIV-infected people treated with highly active
antiretroviral therapy: evidence from the Italian cohort of antiretroviral-naive patients study.
JAIDS 2006;41(1):23-30.
60 The PLATO Collaboration. Predictors of trend in CD4-positive T-cell count and mortality
among HIV-1-infected individuals with virological failure to all three antiretroviral-drug
classes. Lancet 2004;364:51-62.
61 Walmsley S, Bernstein B, King M, et al, and the M98-863 Study Team. Lopinavir-ritonavir
versus nelfinavir for initial treatment of HIV infection. N Engl J Med 2002;346(26):2039-46.
62 King MS, Brun AC, Kempf DJ. Relationship between adherence and the development of
resistance in antiretroviral-naive, HIV-infected patients receiving lopinavir/ritonavir or
nelfinavir. J Infect Dis 2005;191:2046-52.
64 Cote HC, Magil AB, Harris M, et al. Exploring mitochondrial nephrotoxicity as a potential
mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral
therapy. Antivir Ther 2006;11(1):79-86.
65 Martinez E, Milinkovic A, Lazzari E, et al. Pancreatic toxic effect associated with co-administration
of didanosine and tenofovir in HIV-infected adults. Lancet 2004;364:65-7.
68 Karrer U, Lederberger B, Furrer H, et al, and the Swiss HIV Cohort Study Group. Dose-
dependent influence of didanosine on immune recovery in HIV-infected patients treated
with tenofovir. AIDS 2005;19(17):1987-94.
117
69 Di Biago A, Beltrame A, Cenderello G, Ferrea G, De Maria A. Stable treatment-experienced
adults receiving tenofovir and didanosine. HIV Clin Trials 2006;7(1):10-15.
75 Saitoh A, Hull AD, Franklin P, Spector SA. Myelomeningocele in an infant with intrauterine
exposure to efavirenz. J Perinatol 2005;25:555-6.
80 Tarantal AF, Castillo A, Ekert JE, et al. Fetal and maternal outcome after administration of
tenofovir to gravid rhesus monkeys (Macaca mulatta). JAIDS 2002;29:207-20.
81 Hazra R, Gafni R, Madlarelli F, et al. Safety, tolerability, and clinical responses to tenofovir
DF in combination with other antiretrovirals in heavily-treatment-experienced HIV-infected
children: data through 48 weeks. 11th Conference on Retroviruses and Opportunistic
Infections, San Francisco, 8−11 February, 2004 (Abstract 928).
84 Leith J, Pilero P, Storfer S, et al. Appropriate use of nevirapine for long-term therapy: reply
to Leith et al. J Infect Dis 2005;192:545-6.
85 Hitti J, Frenkel LM, Stek AM, et al. Maternal toxicity with continuous nevirapine in pregnancy:
results from P1022. JAIDS 2004;36:772-6.
90 Stern JO, Love JT, Robinson PA, et al. Hepatic safety of nevirapine: results of the Boehringer
Ingelheim Viramune Hepatic Safety Project. XIV International AIDS Conference. 7−12 July
2002, Barcelona (Abstract LBOr15).
91 Leith J, Pilero P, Storfer S, et al. Appropriate use of nevirapine for long-term therapy. J Inf
Dis 2005;192:545-6.
92 Joao EC, Calvet GH, Menezes JA, et al. Nevirapine toxicity in a cohort of HIV-1-infected
pregnant women. Am J Obstet Gynecol 2006;194:199-202.
119
97 Palombi L, Germano P, Liotta G, et al. HAART in pregnancy: safety, effectiveness, and
protection from viral resistance: results from the DREAM cohort. 12 th Conference on
Retroviruses and Opportunistic Infections, Boston, Massachusetts, 22−25 February 2005
(Abstract 67).
99 Centers for Disease Control and Prevention. Serious adverse events attributed to nevirapine
regimens for postexposure prophylaxis after HIV exposures – worldwide, 1997−2000.
MMWR 2001;49:1153-60.
100 Patel SM, Johnson S, Belknap SM, et al. Serious adverse cutaneous and hepatic toxicities
associated with nevirapine use by non-HIV infected individuals. JAIDS 2004;35:120-5.
101 Danel C, Moh R, Anzian A, et al. Tolerance and acceptability of an efavirenz-based regimen
in 740 adults (predominantly women) in West Africa. JAIDS 2006;42:29-35.
102 Stek A, Mirochnick M, Capparelli E, et al. Reduced lopinavir exposure during pregnancy:
preliminary results from P1026s. XV International AIDS Conference, Bangkok, 11−16 July
2004 [Abstract LbOrB08].
103 Lyons FE, Coughlan S, Byrne CM, et al. Emergence of antiretroviral resistance in HIV-
positive women receiving combination antiretroviral therapy in pregnancy. AIDS 2005;19:63-
7.
104 Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of resistance mutations in
women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET
012). AIDS 2001;184:914-7.
105 Lee EJ, Kantor E, Zijenah L, et al. Breast-milk shedding of drug-resistant HIV-1 subtype C
in women exposed to single-dose nevirapine. J Infect Dis 2005;192 (in press).
106 Cunningham CK, Chaix ML, Rackacewicz C, et al. Development of resistance mutations in
women receiving standard antiretroviral therapy who received intrapartum nevirapine to
prevent perinatal human immunodeficiency virus type 1 transmission: a substudy of
Pediatric AIDS Clinical Trials Group protocol 316. J Infect Dis 2002;186:181-8.
107 Lyons FE, Coughlan S, Byrne CM, et al. Emergence of antiretroviral resistance in HIV-
positive women receiving combination antiretroviral therapy in pregnancy. AIDS 2005;19:63-
7.
108 Eshleman SH, Guay LA, Wang J, et al. Distinct patterns of emergence and fading of K103N
and Y181C in women with subtype A vs D after single dose nevirapine: HIVNET 012. JAIDS
2005;40:24-9.
109 Eshleman SH, Hoover DR, Chen S, et al. Nevirapine (NVP) resistance in women with HIV-1
subtype C, compared with subtypes A and D, after administration of single-dose NVP. J
Infect Dis 2005;192:30-6.
111 Flys T, Nissley DV, Claason CW, et al. Sensitive drug-resistance assays reveal long-term
persistence of HIV-1 variants with the K103N nevirapine (NVP) resistance mutation in some
women and infants after the administration of single-dose NVP: HIVNET 012. J Infect Dis
2005;192:24-9.
112 McIntyre J, Martinson N, Investigators for Trial 1413, et al. Addition to short course combivir (CBV)
to single dose viramune (sdNVP) for prevention of mother-to-child transmission (MTCT) of HIV-1
can significantly decrease the subsequent development of maternal NNRTI-resistant virus. XV
International AIDS Conference, Bangkok, 11−16 July 2004 (Abstract LbOrB09).
113 Chaix ML, Dabis F, Ekouevi D, et al. Addition of 3 days of AZT + 3TC postpartum to a short
course of AZT + 3TC and single-dose NVP provides low rate of NVP resistance mutations and
high efficacy in preventing peri-partum HIV-1 transmission: ANRS DITRAME Plus, Abidjan, Côte
d’Ivoire. 12th Conference on Retroviruses and Opportunistic Infections. Boston, February 2005
[Abstract 72LB].
114 Cressey TR, Jourdain G, Lallemant MJ, et al. Persistence of nevirapine exposure during the
postpartum period after intrapartum single-dose nevirapine in addition to zidovudine prophylaxis
for the prevention of mother-to-child transmission of HIV-1. JAIDS 2005;38:283-8.
116 Giuliano M, Palmisano L, Galluzzo CM, et al. Selection of resistance mutations in pregnant
women receiving zidovudine and lamivudine to prevent HIV perinatal transmission. AIDS
2003;17:1570-1.
117 Sullivan J. South African Intrapartum Nevirapine Trial: selection of resistance mutations. XIV
International Conference on AIDS. Barcelona 7−12 July 2002 [Abstract. LbPeB9024].
119 Lockman S, Smeaton LM, Shapiro RL, et al. Maternal and infant response to nevirapine (NVP)-
based antiretroviral treatment (ART) following peripartum single-dose NVP or placebo (Plc).
Infectious Disease Society of America, San Francisco, October 2005 (in press).
120 Girardi E, Palmieri F, Cingolani A. et al, Changing clinical presentation and survival in HIV-
associated tuberculosis after highly active antiretroviral therapy, JAIDS 2001;26(4):326-31.
121 Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of
tuberculosis in South Africa: a cohort study. Lancet 2002;359(9323):2059-64.
121
122 Kwara A, Flaning T. Highly active antiretroviral therapy (HAART) in adults with tuberculosis:
current status. Int J Tuberc Lung Dis 2005;9(3):248-57.
123 WHO. Interim policy on TB/HIV collaborative activities. Geneva: WHO; 2004. http://www.
who.int/hiv/pub/tb/tbhiv/en/
124 Corbett EL, Watt C, Walker N, et al. The growing burden of tuberculosis: global trends and
interactions with the HIV epidemic. Arch Intern Med 2003;163(9):1009-21. http://www.fda.
gov/medwatch/safety/2005/Sustiva_DHCPletter-061005.pdf
125 Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral
agents in HIV-infected adults and adolescents. 6 October 2005. http://AIDSinfo.nih.gov .
126 Shao H, Crump1 J, et al. A randomized trial of early vs delayed fixed-dose combination zidovudine/
lamivudine/abacavir in patients co-infected with HIV and tuberculosis: early findings of the
Tuberculosis and HIV Immune Reconstitution Syndrome Trial. Poster, CROI 2006.
127 Almond L, Gibbons S, Davies G, Dack D, Khoo S. A retrospective survey of the Liverpool
TDM Service: factors influencing efavirenz concentrations in patients taking rifampicin. 6th
International Workshop on Clinical Pharmacology of HIV Therapy, Quebec, April 2005
(Poster 2.12).
128 Patel A, Patel K, Patel J, et al. Safety and antiretroviral effectiveness of concomitant use of
rifampicin and efavirenz for antiretroviral-naive patients in India who are coinfected with
tuberculosis and HIV-1. JAIDS 2004;37(1):1166-9.
129 Pedral-Sampaio D, et al. Efficacy and safety of efavirenz in HIV patients on rifampin for
tuberculosis. The Brazilian Journal of Infectious Diseases 2004;8(3):211-6.
130 Manosuthi W, et al. A randomized controlled trial of efavirenz 600 mg/day versus 800 mg/day
in HIV-infected patients with tuberculosis to study plasma efavirenz level, virological and
immunological outcomes: a preliminary result. XV International AIDS Conference, Bangkok,
July 2004 (Abstract MoOrB1013).
131 Sheehan NL, Richter C. Efavirenz 600 mg is not associated with subtherapeutic efavirenz
concentrations when given concomitantly with rifampin. 6 th International Workshop on
Clinical Pharmacology of HIV therapy, Quebec, 28−30 April 2005.
132 Autar RS, et al. What is the clinical relevance of the drug interaction between nevirapine and
rifampin? XV International AIDS Conference, Bangkok, July 2004 (Abstract B11784).
133 Oliva J, et al. Co-administration of rifampin and nevirapine in HIV-infected patients with
tuberculosis. AIDS 2003;17:637-42.
134 Ribera E, et al. Pharmacokinetic interaction between nevirapine and rifampin in HIV-infected
patients with tuberculosis. JAIDS 2001;28:450-3.
135 Dean GL, Back DJ, De Ruiter A. Effect of tuberculosis therapy on nevirapine trough plasma
concentrations. AIDS 1999;13:2489-90.
139 Lawn SD. Bekker L, Miller RF. Immune reconstitution disease associated with mycobacterial infections
in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;(6):361-73.
140 Williams B, Dye C. Antiretroviral drugs for tuberculosis control in the era of HIV/AIDS.
Science 2003;301:1535-7.
141 Scano F, Toskin I, Nunn P. Immunological status and prognosis of HIV-infected patients with
active tuberculosis. 3 rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janeiro,
24−27 July 2005.
142 Seyler C, Toure S, Messou E. Risk factors for active tuberculosis after antiretroviral treatment
initiation in Abidjan. Am J Respir Crit Care Med 2005;172(1):123-7.
143 Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in
the era of highly active antiretroviral therapy. AIDS 2002;16(1):75-83.
144 Justesen US, Andersen AB, Klitgaard NA et al. Pharmacokinetic interaction between
rifampicin and the combination of indinavir and low dose ritonavir in HIV infected patients.
Clin Infect Dis 2004;38(3):426-9.
145 la Porte CJ, Colbers EP, Bertz R, et al. Pharmacokinetics of adjusted-dose lopinavir-ritonavir
combined with rifampin in healthy volunteers. Antimicrob Agents Chemother 2004;48(5):1553-
60.
146 Roche Laboratories. Important drug interaction warning. February 2005 (letter). http://www.
thebody.com/fda/pdfs/rifampin_letter.pdf
147 Losso H, et al. The use of saquinavir/ritonavir 100/100 mg twice daily in patients with
tuberculosis receiving rifampin. Antiviral Therapy 2004;9:1031-3.
148 Vieira M. Phase IV clinical trial to access the efficacy and safety of concomitant use of
ritonavir-saquinavir (400mg/400mg) and rifampicin to treat tuberculosis and AIDS. Personal
communication.
123
150 The Global Burden of Hepatitis C Working Group. Global Burden of Disease (GBD) for
Hepatitis C. Jf Clin Pharmacol 2004;44:20-9.
151 Dore GJ, Cooper DA. The impact of HIV therapy on co-infection with hepatitis B and
hepatitis C viruses. Curr Opin Infect Dis 2001;14:749-55.
153 Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in human immunodeficiency
virus and hepatitis C virus coinfected patients. Hepatology 1999;30:1054-8.
154 Pol S, Vallet-Pritchard A, Fontaine H. Hepatitis C and human immune deficiency coinfection
at the era of highly active antiretroviral therapy. J Viral Hepatitis 2002;9:1-8.
155 Piroth L, Duong M, Quantin C, et al. Does hepatitis C virus coinfection accelerate clinical
and immunological evolution of HIV-infected patients? AIDS 1998;12:381-8.
156 Sabin CA, Telfer P, Phillips AN, Bhagani S, Lee CA. The association between hepatitis C
virus genotype and human immunodeficiency virus. Disease progression in a cohort of
hemophilic men. J Infect Dis 1997;175:164-8.
158 Rockstroh JK. Influence of viral hepatitis on HIV infection. J Hepatol 2006;44(Suppl 1):S25.
159 Rockstroh JK, Mocroft A, Soriano V, et al, and the EuroSIDA Study Group. Influence of
hepatitis C virus infection on HIV-1 disease progression and response to highly active
antiretroviral therapy. J Infect Dis 2005;192(6):992-1002.
160 Benhamou Y, Fleury H, Trimoulet P, et al, and TECOVIR Study Group. Anti-hepatitis B virus efficacy of
tenofovir disoproxil fumarate in HIV-infected patients. Hepatology 2006;43(3):548-55.
161 Matthews GV, Bartholomeusz A, et al. Characteristics of drug resistant HBV in an international
collaborative study of HIV-HBV-infected individuals on extended lamivudine therapy. AIDS
2006;20(6):863-70.
162 Nelson M, Portsmounth S, Stebbing J, et al. An open-label study of tenofovir in HIV-1 and
hepatiis B virius co-infected patients. AIDS 2003;17:F7-10.
163 Dore GJ, Cooper DA, Pozniank AL, et al, and the 903 and 907 Study Teams. Efficacy of
tenofovir disoproxil fumarate in antiretroviral therapy-naive and -experienced patients co-
infected with HIV-1 and hepatitis B virus. J Infect Dis 2004;189:1885-92.
164 Nelson M, Bhagani S, Fisher M, Leen C, Brook S, et al. A 48-week study of tenofovir or
lamivudine or a combination of tenofovir and lamivudine for the treatment of chronic hepatitis
B in HIV/HBV-co-infected individuals. 13 th Conference on Retroviruses and Opportunistic
Infections, Denver, Colorado, 5−8 February 2006 (Abstract 831).
167 Dominguez S, Ghosn J, et al. Efficacy of early treatment of acute hepatitis C infection with
pegylated interferon and ribavirin in HIV-infected patients. AIDS 2006;20(8):1157-61.
168 Alberti A, Clumack N, et al Short statement on the first European Consensus Conference
on the Treatment of Chronic Hepatic B and C in HIV Coinfected Patients. Journal of
Hepatology 2005;42:615-24.
169 Mocroft A, Rockstroh J, Soriano V, et al, and the EuroSIDA Study Group. Are specific
antiretrovirals associated with an increased risk of discontinuation due to toxicities or
patient/physician choice in patients with hepatitis C virus coinfection? Antivir Ther
2005;10(7):779-90.
170 Aceijas C, Stimson GV, Hickman M, Rhodes T. Global overview of injecting drug use and
HIV infection among injecting drug users. AIDS 2004;18:2295-303.
171 Kohli R, Lo Y, Howard AA, et al. Mortality in an urban cohort of HIV-infected and at-risk drug
users in the era of highly active antiretroviral therapy Clin Infect Dis 2005;41:864-72.
172 Wood E, Montaner JS, Yip B, et al. Adherence and plasma HIV RNA responses to highly
active antiretroviral therapy among HIV-1 infected injection drug users. Canadian Medical
Association Journal, 2003;169(7):656-61.
173 Wood E, Hogg RS, Yip B, et al. Rates of antiretroviral resistance among HIV-infected
patients with and without a history of injecting drug use. AIDS 2005;19:1189-95.
174 Aceijas C, Oppenheimer E, Stimson GV, et al. Antiretroviral treatment for injecting drug users in
developing and transitional countries one year before the end of the “Treating 3 million by 2005.
Making it happen. The WHO strategy” (3b y5). Addiction 2006 (in press).
175 Wood E, Montaner JS, Yip B, et al. Adherence to antiretroviral therapy and CD4 T-Cell count
responses among HIV-infected injection drug users. Antiviral Therapy 2004;9(2):229-35.
176 Lucas GM, Weidle PJ, Hader S, Moore RD. Directly administered antiretroviral therapy in an
urban methadone maintenance clinic: a nonrandomized comparative study. Clin Infect Dis
2004;38(Suppl 5):S409-S413.
177 International Harm Reduction Association. Role of harm reduction petworks in scaling up
ARV to IDUs as part of the WHO ‘3by 5’ initiative. Project report prepared by Edna
Oppenheimer and submitted by IHRA to WHO. May 2004.
178 McCance-Katz EF, Rainey PM, Friedland G, Kosten TR, Jatlow P. Effect of opioid dependence
pharmacotherapies on zidovudine disposition. American Journal of Addictions
2001;10(4):296-307.
125
179 McCance-Katz EF, Pade P, Friedland G, Morse G, Moody D, Rainey P. Efavirenz decreases
buprenorphine exposure, but is not associated with opiate withdrawal in opioid dependent
individuals. 12 th Conference on Retroviruses and Opportunistic Infections, Boston,
Massachusetts, 22−25 February 2005 (Abstract 653).
180 Gordillo V, del Amo J, et al. Sociodemographic and psychological variables influencing
adherence to antiretroviral therapy. AIDS 1999;10(13):1763-9.
181 Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, Squier C, et al. Adherence to
protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med
2000;133(1):21-30.
182 Weiser S, Wolfe W, et al; Adherence is not a barrier to successful antiretroviral therapy in
South Africa. AIDS 2003;17:1369-75.
183 Rowe K, Makhubele B, et al. Adherence to TB preventive therapy for HIV positive patients
in rural South Africa: Implications for antiretroviral delivery in resource poor settings. Int J
Tuberc Lung Dis. 2005;3:263-9.
184 Liu H, Miller L, et al. Repeated measures longitudinal analyses of HIV virologic response as
a function of percent adherence, dose timing, genotypic sensitivity, and other factors.
JAIDS 2006;41(3):315-22.
186 World Health Organization. WHO discussion paper: the practice of charging user fees at the
point of service delivery for HIV/AIDS treatment and care. Geneva: WHO; 2005. Available
from: http://www.who.int/hiv/pub/advocacy/ freeaccess/en/index.html
187 Laniece I, Ciss M, Adherence to HAART and its principal determinants in a cohort of
Senalese adults. AIDS 2003;17(Suppl 3),S103-8.
188 Weiser S, Wolfe W, et al. Barriers to antiretroviral adherence for patients living with HIV
infection and AIDS in Botswana. JAIDS 2003;34:281-8.
191 WHO. Patient monitoring guidelines for HIV care and antiretroviral therapy. Geneva: World
Health Organization; 2005.
194 Cressey TR, Leenasirimakul P, Jourdain G, et al. Low doses of indinavir boosted with
ritonavir in HIV-infected Thai patients: pharmacokinetics, efficacy and tolerability. J
Antimicrob Chemother 2005;(6):1041-4.
196 Duvivier C, Myrto A, Marcelin AG et al. Efficacy and safety of ritonavir/indinavir 100/400 mg
twice daily in combination with two nucleoside analogues in antiretroviral treatment-naive
HIV-infected individuals. Antivir Ther. 2003 8(6):603-9.
198 Tindyebwa D, Kayita J, Musoke P, Eley B, Nduati R, Coovadia H, et al. African Network for
the Care of Children Affected by AIDS. Handbook on Paediatric AIDS in Africa Kampala,
Uganda; 2004.
127
ANTIRETROVIR AL THER APY FOR HIV INFECTION
128 IN ADULTS AND ADOLESCENTS
Photograph: Gideon Mendel/The International HIV/AIDS Alliance/Corbis